O Dr. William Masters, o mais famoso obstetra e ginecologista da Universidade de Washington, gerencia um consultório de sucesso durante o dia e conduz um estudo secrego ligado à sexualidade humana à noite. A ex-cantora da noite Virginia Johnson se junta ao secretariado do hospital e acaba se tornando um trunfo para o trabalho de Masters.

Ao ser convidada para participar do estudo ao lado de Masters, Johnson considera a melhor forma de manter seu emprego, e logo descobre que não mais o possui. Enquanto Johnson luta para manter seu sustento e de sua família, Masters leva seu estudo para um bordel, mas logo descobr que o caos impera sem a ajuda de Johnson.

Masters e Johnson seguem com o estudo no bordel, mas circunstâncias convencem o médico a levar tudo de volta ao hospital. Lá, Johnson se surpreende em saber que a nova obstetra é uma mulher nada solidária. Enquanto isso, Libby luta para conceber e Ethan consegue o caso de sua vida.

Masters e Johnson recrutam novos participantes no campus para o estudo. No entanto, Virginia fica mesmo chocada quando seu ex-marido resolve se voluntariar. Já Masters recebe a visita da mãe e revive memórias dolorosas da infância. Para completar, a Libby tenta juntar Virginia e Ethan, mas as coisas não saem conforme o planejado.

O estudo se expande para a inclusão de casais, o que faz com que Masters e Johnson descubram que a ciência do sexo se complica com os mistérios da atração. Enquanto Johnson tenta se reaproximar do filho, Masters experimenta a ansiedade de se tornar pai. Para completar, Ethan pode ter problemas com sua carreira médica.

Após o aborto, Libby e Masters viajam para Miami para relaxar, porém o marido é levado de volta ao trabalho. Sozinha no hospital, Veronica chama Jane para tentar acabar com a teoria de Freud que um tipo de orgasmo feminino é melhor que outros.

Masters e Johnson continuam com o estudo - dessa vez como participantes - mas Virginia acha que isso pode interferir com a vida pessoal do médico. Libby pressiona Haas a reiniciar seu tratamento de fertilidade em segredo. Já Haas luta para esquecer Virginia, enqunto Scully confronta o marido sobre os problemas do casamento.

Masters e Johnson acreditam que é preciso filmagem para conseguir o melhor resultado no estudo, mas para isso eles precisarão de ajuda de fora. Johnson retoma os estudos e vê obstáculos no caminho, enquanto Haas e Langham falam sobre os méritos do casamento.

Quando Masters e Johnson decidem filmar reações externas para o estudo, eles precisam convencer Lester e Jane que a gravação não cruzará a fronteira rumo à pornografia. Enquanto isso, os planos de Vivian sobre se casar na igreja presbiteriana vão por água abaixo quando Haas revela ser judeu. Libby mantém sua gravidez em segredo. Para completar, Estabrooks vê a relação íntima de Virginia e Will.

Conflitos entre os integrantes do hospital aumentam. Enquanto isso, uma participante do estudo revelar estar grávida e quer saber a identidade do pai, ao mesmo tempo em que Masters e Johnson decidem o futuro da relação. Já Haas descobre que não conseguiu um trabalho no hospital e presume, erroneamente, que a resposta está relacionada ao término com Vivian.

Com Johnson fora do time, Masters aceita a oferta de Libby par compilar o estudo para uma apresentação no hospital. Enquanto isso, o Dr. DePaul e Johnson viajam para uma convenção médica. Para completar, o ex de Virginia volta e descobre Ethan bancando o pai de seu filho.

Quando Masters tenta provocar na apresentação para o hospital e mostra uma filmagem do orgasmo feminino, a resposta não é a esperada. Enquanto isso, Haas analisa uma oferta de emprego na UCLA e considera o que essa mudança fará com sua relação com Virginia. Para completar, Scully tenta o tratamento de eletrochoque para curar a homossexualidade.

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.