Dr. William Masters, o mais importante OB/GYN da Universidade de Washington, administra uma prática médica bem-sucedida durante o dia e conduz um estudo secreto da sexualidade humana à noite. A ex-cantora de boate Virginia Johnson se junta à equipe de secretaria do hospital e prova ser um trunfo para o trabalho de Masters.

Seguindo a proposta de Masters de que eles participassem do estudo de resposta sexual, Johnson considera o melhor curso de ação para manter seu emprego - apenas para descobrir que ela não tem mais um. O estudo foi forçado a sair do hospital e Masters acredita que Johnson é o culpado. Enquanto Johnson luta para salvar seu emprego e se esforça para cuidar de seus filhos, Masters muda seu escritório para um bordel. Mas Masters logo descobre que o caos do bordel é incontrolável sem a ajuda de Johnson.

Masters e Johnson continuam suas pesquisas no bordel, mas dados distorcidos confirmam que Masters deve levar o estudo de volta ao hospital. No hospital, Johnson fica surpreso ao saber que uma nova médica ilustre no andar de OB/GYN é uma mulher que não tem interesse na solidariedade feminina. Enquanto isso, Libby luta para engravidar e o Dr. Ethan Haas recebe o caso de sua vida - uma mulher grávida de quadrigêmeos.

Com o estudo de volta ao hospital, Masters e Johnson recrutam novos participantes no campus. Mas Johnson fica chocada quando seu ex-marido George, que está dormindo em seu sofá, quer se inscrever. A mãe de Masters vem visitá-lo, mas sua nova visão de vida desperta lembranças dolorosas de sua infância. E a tentativa de Libby de bancar a casamenteira com Virginia e Ethan não corre tão bem quanto ela esperava.

Quando Masters e Johnson expandem o estudo para incluir casais, eles descobrem que a ciência do sexo é facilmente complicada pelo mistério da atração. Johnson tenta se conectar com seu filho, que prefere o pai. Antecipando a chegada iminente de seu bebê, Masters sente ansiedade em se tornar pai. E o Dr. Ethan Haas descobre que namorar a filha do reitor pode afetar sua carreira médica.

Após o aborto espontâneo, Libby e Masters viajam para Miami para descansar e relaxar, mas Masters é atraído de volta ao trabalho por um casal sexualmente aventureiro que mora ao lado. Sozinha no hospital, Virginia convoca Jane para tentar desmascarar a teoria de Freud de que um tipo de orgasmo feminino é melhor do que outro. E Langham encontra uma cura improvável para sua disfunção sexual em Margaret Scully.

Masters e Johnson continuam seu estudo de resposta sexual – agora como participantes – mas Johnson teme que seu trabalho possa estar interferindo na vida doméstica de Masters. Libby pressiona a Dra. Haas a retomar seus tratamentos de fertilidade em segredo. Enquanto isso, Haas luta para deixar de lado os sentimentos por Virginia enquanto seu relacionamento com Vivian se aprofunda. E Margaret Scully, apanhada em sua infidelidade, confronta o marido sobre os crescentes problemas em seu casamento.

Masters e Johnson decidem que a melhor maneira de registrar as descobertas de seus estudos é filmá-los, mas para isso precisam de ajuda externa. Johnson redobra seus esforços para obter um diploma universitário, apenas para descobrir que a aula de anatomia básica do Dr. DePaul é um requisito. Enquanto isso, Haas e Langham – ambos inseguros em seus relacionamentos – se convencem dos méritos de ser um homem casado. E depois que Margaret o pega em uma posição comprometedora, Scully toma medidas drásticas para controlar seus impulsos sexuais.

Quando Masters e Johnson decidem filmar reações externas no estudo, eles devem convencer Lester e Jane de que suas filmagens não cruzarão a linha da pornografia. Os planos de Haas e Vivian para um casamento na igreja presbiteriana são desviados quando Haas revela que é judeu. Libby mantém sua gravidez em segredo de Masters e, em vez disso, o encoraja a consertar seu relacionamento com sua mãe. Mas durante visitas noturnas ao hospital, Estabrooks observa o relacionamento íntimo de Masters e Johnson.

O hospital participa de um exercício nacional de defesa civil, e a atmosfera intensificada aumenta os conflitos entre a equipe. Uma ex-participante do estudo revela que está grávida e quer saber a identidade do pai. Masters e Johnson, com seu relacionamento tenso após o término de sua participação no estudo, discutem se devem manter a confidencialidade do estudo ou assumir a responsabilidade. Haas descobre que lhe foi negado um futuro emprego no hospital, mas erroneamente assume que seu rompimento com Vivian é o culpado. Margaret Scully busca respostas sobre a sexualidade de seu marido em uma fonte improvável.

Com Johnson não mais em sua equipe, Masters aceita a oferta de Libby para ajudar a compilar o trabalho de estudo para uma apresentação em todo o hospital. Mas quando Masters vê a apresentação de outro médico colocar seus colegas para dormir, ele fica determinado a chamar a atenção deles, mesmo que isso signifique avançar em pesquisas provocativas, mas incompletas. Dr. DePaul e Johnson viajam para uma convenção médica e DePaul fala sobre por que seu trabalho no exame de Papanicolaou é tão importante. E o ex-marido de Virginia, George, retorna para encontrar Ethan Haas bancando o pai de seus filhos.

O trabalho de Masters sobre a sexualidade humana culmina com uma apresentação em todo o hospital dos resultados da pesquisa dele e de Johnson. Mas quando Masters tenta ir além com a filmagem externa do orgasmo feminino, a resposta dos médicos ao filme não é o que ele esperava. Enquanto isso, Haas aceita uma oferta de emprego no Hospital da UCLA e considera o que uma mudança significaria para seu relacionamento com Virginia. Scully busca um tratamento de eletrochoque na esperança de curar sua homossexualidade, mas Margaret tem dúvidas sobre os riscos envolvidos.

Masters deals with the ramifications of his disastrous presentation and being fired from the hospital. Meanwhile, Libby urges Masters to get another job; and Virginia fights off advances and innuendos stemming from the belief that she was the woman in Master's explicit film.

Masters begins a new job at Memorial Hospital under Betty's extortion terms only to discover that his boss insists he leave Virginia behind in favor of a handpicked secretary. Meanwhile, Johnson is torn between pressing Masters to rehire her and staying by DePaul's side as her condition worsens.

Masters delivers a baby with ambiguous genitalia and urges the parents not to surgically assign the child a sex out of fear or convenience. Meeting Virginia at a hotel for a secret rendezvous, the two of them divide their attention between sexual role-play and a championship boxing match, prompting Virginia to unearth the truth of Masters'' troubled childhood.

Langham observes Masters and Johnson exiting a hotel room and shares his suspicions with DePaul, who is forced to make plans for her work without Virginia's involvement. Meanwhile, Betty attempts to conceal her infertility from Gene; and Masters tries to bring Johnson aboard as his assistant only to be thwarted by the head of the hospital, who takes a prurient interest in Masters' study.

Masters continues to break new ground by continuing his study as the only white physician in a Negro hospital but at the cost of his gynecology practice. Libby is confronted by Coral's boyfriend, Robert, over her poor treatment of Coral, Betty reunites with her former lover, and Johnson struggles to right her relationship with DePaul - who is newly aware of Johnson's ongoing affair with Masters.

After Hendricks bans Masters from using black participants in his study, Masters contacts a journalist to promote his efforts, using the debunking of sexual stereotypes as the lure. Johnson is forced to accept DePaul's choice to end her chemotherapy treatments. Gene uncovers the truth about Betty and Helen's relationship. Libby fires Coral after discovering she lied about Robert.

In the wake of Masters' discovery that Johnson has continued to have romantic relationships with other men, he becomes impotent without her knowledge and cuts off their sexual work together. He tries to keep his new clinic solvent over the course of three years by borrowing against his house, offering medical services to the hotel - and finally accepting money from his mother.

Masters privately treats a couple for infertility, without revealing his relationship to them. Johnson realizes her work with Masters can be used to help people suffering from sexual dysfunction - but quickly gets in over her head when she attempts to treat Barbara Sanderson on her own. Libby is unnerved after witnessing a hate crime that is then whitewashed by the police.

Virginia continues to impersonate a patient's case history in order to glean advice from a psychiatrist. Betty and Masters' attempt to remedy Lester's impotence by hiring a prostitute rattles him even further. Libby gets the third degree when she offers her eyewitness testimony regarding the beaten man. And Barbara Sanders wrestles with an unsettling diagnosis that exposes a chain of secrets and causes Masters and Johnson to clash over their treatment strategy.

Masters learns of a rival study and calls in a public relations expert to help brand his work with Johnson. Virginia, having finally learned of Masters' sexual difficulties, is invigorated by the prospect of finding a cure. Determined to prove her worth to Robert, Libby canvases a tenement for a rent strike. Plus, Langham is stunned when Flo informs him that he has to have sex with her in order to keep his job. And Barbara and Lester connect over their shared sexual dysfunctions.

A television crew arrives at the clinic to document Masters and Johnson's work treating sexual dysfunction. Masters considers the publicity premature, and himself unsuitable as a television presence. Virginia deals with the fallout of having prioritized her work over her parenting when George argues to take their children on a trip with his new wife. Plus, Libby finds in Robert an appreciation for what she has to offer. And Langham realizes there's no way out of his sexual contract with Flo.

After watching an early cut of the documentary, Masters is disturbed by the portrayal of his work. Johnson's move to solidify her custody arrangement with George backfires. Finding justification in Masters' distraction, Libby continues her relationship with Robert. Langham discovers Flo's family's wealth and connections, causing him to re-evaluate his relationship with her. And after repeated testing of their protocol to cure impotence, Masters and Johnson feel they are ready to cure sexual dysfunction.

Masters and Johnson face the press for the first time.

Masters takes on a high profile patient. Virginia and Libby come to terms.

Masters and Johnson look to capitalize on their burgeoning fame.

Masters seeks unexpected advice. Virginia is distracted by news of Henry.

Johnson's parents arrive unannounced. Masters takes on a promising patient.

Masters and Johnson take on a famous couple hoping to renew their sex life.

Masters and Johnson are interviewed as they take on an exotic new patient.

Johnson jets away with Dan Logan. Masters begins his surrogacy program.

Masters continues his surrogacy program, now under Johnson's critical eye.

Johnson objects to Masters' program following missteps in the protocol.

Agendas collide as Masters, Johnson, Logan and his wife meet for a dinner.

Masters and Johnson find their life's work in jeopardy. Season finale.

In the wake of their fallout, Masters and Johnson search for purpose in a world without one another and look to work as their personal lives crash down around them. Libby finds herself alone for the first time since her marriage and discovers some unexpected allies. Season premiere.

Masters and Johnson turn to new partners in an effort to put the past behind them and focus on their expanding clinic. Given their fractured triangle, Libby reevaluates her relationship with Bill and Virginia.

Masters and Johnson adjust to new partners, but their respective cases have them second-guessing the instinct to remain separated. A romantic prospect pushes Libby to embrace life as a newly single woman of the sexual revolution.

Johnson, Masters, Libby and Keller wind up together at a party thrown by Art and Nancy. Pairings and perspectives shift as the night wears on, until the light of day exposes the consequences of the evening.

Johnson and Masters' troubles come to a head as the trial begins with Keller leading the charge. Virginia does her best to revive their career as Bill faces the reality of what the charges could mean for him, Johnson and the practice.

Johnson looks to get her relationship with Masters back on track while Masters does his best to find satisfaction elsewhere. Betty and Helen ready themselves for a new addition; Art and Nancy discuss the consequences of their party.

Masters looks to groom Art as his protege in a new area of research as Johnson does her best to keep Nancy at arm's length. Betty seeks an unlikely source for assistance in her fight for equal rights to Helen's baby.

Masters and Johnson go on the road and pose as a couple to investigate practices at a competing clinic. While Bill and Virginia are away, Art, Nancy and Langham take advantage of their absence to further their own agendas.

Masters and Johnson return from Topeka, each grappling with the trip's ramifications. Art and Nancy look to tie up loose ends in order to have a fresh start, and Libby embarks on a road trip with Bram that changes her perspective.

Masters and Johnson work to save the practice from disintegrating in the face of insurrection within the clinic. As everyone in their lives either moves on or falls away, Bill and Virginia find solace in one another. Season finale.