Dr. William Masters (Michael Sheen) proposes a controversial study of human sexuality but is rejected by his university. Undaunted, he begins the study anyway and hires Virginia Johnson (Lizzy Caplan), a nightclub singer-turned-secretary, as his assistant. Upon learning that their sole subject, prostitute Betty DiMello (Annaleigh Ashford), is a lesbian, Johnson sets about recruiting additional female and male subjects, including Masters' colleague Dr. Austin Langham (Teddy Sears). She enters into a sexual relationship with Dr. Ethan Haas (Nicholas D'Agosto) but he becomes overly attached and eventually physically abusive. Masters induces his wife Libby (Caitlin Fitzgerald) to undergo painful and invasive infertility treatments, despite, according to Haas, Masters being the infertile one. Masters suggests that he and Johnson defuse possible "sexual transference" by having sex with each other as part of the study.