Dr. William Masters, Washington University’s foremost OB/GYN, runs a successful medical practice by day and conducts a secret study of human sexuality by night. Former nightclub singer Virginia Johnson joins the hospital secretarial staff and proves herself to be an asset to Masters’ work.

On the heels of Masters’ proposal that they participate in the sexual response study, Johnson considers the best course of action to keep her job – only to find she no longer has one. The study has been forced out of the hospital and Masters believes Johnson is to blame. As Johnson fights to save her job and struggles to care for her kids, Masters moves his study to a brothel. But Masters soon discovers that the chaos of the cathouse is unmanageable without Johnson’s help.

Masters and Johnson continue their research in the brothel but skewed data confirms that Masters must get the study back into the hospital. At the hospital, Johnson is surprised to learn that a distinguished new doctor on the OB/GYN floor is a woman who has no interest in female solidarity. Meanwhile, Libby struggles to conceive and Dr. Ethan Haas gets the case of a lifetime – a woman pregnant with quadruplets.

When Masters and Johnson expand the study to include couples, they discover that the science of sex is easily complicated by the mystery of attraction. Johnson tries to connect with her son who prefers his dad. In anticipation of his baby’s impending arrival, Masters experiences anxiety about becoming a father. And Dr. Ethan Haas learns that dating the provost’s daughter could impact his medical career.

In the aftermath of the miscarriage, Libby and Masters travel to Miami for some much needed rest and relaxation, but Masters is drawn back into his work by a sexually adventurous couple next door. Alone in the hospital, Virginia enlists Jane in an effort to debunk Freud’s theory that one kind of female orgasm is better than another. And Langham finds an unlikely cure for his sexual dysfunction in Margaret Scully.

Masters and Johnson continue their sexual response study – now as participants – but Johnson fears their work may be interfering with Masters’ home life. Libby pressures Dr. Haas to resume her fertility treatments in secret. Meanwhile, Haas struggles to let go of feelings for Virginia as his relationship with Vivian deepens. And Margaret Scully, caught in her infidelity, confronts her husband on the mounting problems in their marriage.

Masters and Johnson decide that the best way to record their study findings is to film them, but to do so they have to enlist outside help. Johnson redoubles her efforts to get a college degree, only to find that Dr. DePaul’s Basic Anatomy class is a requirement. Meanwhile, Haas and Langham – both unsure in their relationships – convince each other of the merits of being a married man. And after Margaret catches him in a compromising position, Scully takes drastic steps to control his sexual impulses.

The hospital takes part in a nationwide civil defense drill, and the heightened atmosphere escalates conflicts among the staff. A former study participant reveals she’s pregnant and wants to know the identity of the father. Masters and Johnson, their relationship strained after ending their study participation, butt heads on whether to maintain study confidentiality or take responsibility. Haas learns he’s been denied a future job at the hospital but wrongly assumes his breakup with Vivian is to blame. Margaret Scully seeks answers about her husband’s sexuality from an unlikely source.

Masters’ work on human sexuality culminates with a hospital-wide presentation of his and Johnson’s research findings. But when Masters attempts to push the envelope with the external footage of the female orgasm, the doctors’ response to the film is not what he had hoped. Meanwhile, Haas entertains a job offer at UCLA Hospital and considers what a move would mean for his relationship with Virginia. Scully pursues electroshock treatment with the hope of curing his homosexuality but Margaret has second thoughts about the risks involved.

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.

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 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.

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

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

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

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 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.