In the first season we meet doctor Bill Masters, a brilliant gynecologist who seems to have the perfect life: a beautiful wife, a brilliant career and even a protégée whom he teaches everything he knows. Masters is praised by all his colleagues and bosses at the Washington University Hospital in St. Louis, and he’s very sought after by his patients. Despite all that, Masters would rather spend his free time at a brothel house offering his medical services in return for him being allowed to watch through a peephole as prostitutes have sex with their clients. That is when we find out that Masters, though he has great knowledge and experience in obstetric surgery, he is more interested in studying human sexuality, a very sensitive subject in 1950’s America. What is more, his seemingly perfect wife, Libby, is very distant and though she desperately wants to have a baby, she and her husband are sleeping in different beds.
Masters’ protégée, Dr. Ethan Haas, is going out with a venturous woman, Virginia Johnson, who soon shows up for an interview for the position of Masters’ secretary. She gets the job despite the fact she’s a divorced mother of two with no university degree. During her interview, Virginia tells Masters that, even though she divorced twice, she thinks that love and sex are not necessarily connected. Intrigued by such a forward thinking woman, Masters hires Virginia on the spot.
Having trouble conceiving, despite trying everything her husband tells her to, Libby starts a new trial with the help of Dr. Haas. But, we soon find out that the reason Libby hasn’t gotten pregnant is because Masters has a low sperm count and not because of her. Libby however is unaware of this fact.
Masters is trying to start a study on human sexuality and he confesses that to his boss and friend Barton Scully. The latter doesn’t think that’s a very good idea and he tells Masters that, if he decides to pitch this idea to the hospital’s board, he’ll be branded as a pervert.
Masters decides to start his study in secrecy with the help of his new secretary, Virginia. He asks for the help of one of the prostitutes at the brothel he usually visits, Betty. Masters fashions a dildo with a camera at the end which records the way the human body reacts when aroused. Masters convinces Scully to watch a woman while masturbating with this device in the hope he might change his mind. In the end, he accepts Masters’ proposal and presents it to the hospital board.
Masters and Virginia begin their study which basely consists in watching and monitoring volunteers as they’re having sex. Masters propositions his secretary to also start having sex with each other in order to interpret the data first hand.
Despite some original setbacks and some differences of opinion between Virginia and Masters, the study becomes larger, and more people are recruited. Jealous of the amount of time Virginia spends with Masters, Ethan Haas breaks up with her and soon starts dating Scully’s daughter, the ingénue Vivian. Though their relationship becomes very serious, very quickly, he decides to break it off and gets back with Virginia. Another female gynecologist starts working at the hospital, Dr. Lillian DePaul, and she inspires Virginia to continue her studies.
Despite their problems, Libby manages to get pregnant, but she loses the baby. She soon resumes her treatments and, in the end, she gets pregnant again.
Scully is not happy with the fact that Masters’ study basically consists of couples having sex while being filmed and attached to medical devices. However, when Masters inadvertently finds out that Scully is gay, he blackmails his boss into letting him continue with his research. Virginia starts spending more time with Dr. DePaul and she becomes interested in other fields of medicine, to Masters’ dismay.
After months of work, he is ready to present their first findings, and though Scully tries to stop him, Masters sets up a hospital wide presentation, without Virginia’s help. She is upset with Masters because he didn’t put her name on the study after all the work she has done for him. Predictably, the hospital staff, and even Libby, are shocked and some even offended by Masters’ study, so he ends up getting fired.
The season ends with Ethan calling Virginia, asking her to get married and move to California with him and her children. He gives her time to think. Libby goes into labor and gives birth, but she doesn’t call her husband. Scully confesses to Masters that he has decided to go through aversion therapy in order to cure the fact that he is gay. In the end, Masters shows up on Virginia’s doorstep apologizing for omitting her name from the study and telling her he cannot live without her.
The second season shows Virginia and Masters sleeping together, all in the name of research, or so they say. Masters is trying and failing to help Libby with the baby, while Virginia works at the hospital with Dr. DePaul at a pap smear campaign. We soon find out that Dr. DePaul has terminal cancer and she dies.
Masters and Virginia constantly meet at a faraway hotel where they rent a room under a fake name. There, they have sex and record the data in order to further their study. Struggling to find a new job, Masters accepts a position at a black hospital and hires Virginia not as his secretary, but as his assistant. However, he is fired from that position as well, so he decides to open a private practice with Virginia. When he finds out that his partner is dating and sleeping with other men, Masters decides to put an end to their affair, especially after he discovers he has become impotent.
The series makes a time jump into 1960. The study has grown, but the relationship between Virginia and Masters is still cold. However, they manage to put their differences aside and resume their intimate relationship, again for the sake of science. Virginia becomes more involved in the research, and even takes a keen interest in patients with sexual dysfunction. In the end, their research shifts from studying human sexuality to trying to cure sexual dysfunctions, including impotence. A television crew is making a documentary about the study, as another doctor is preparing to launch a book on the same subject.
Meanwhile, Libby becomes more involved in the civil rights movement, trying to help the black community, and ends up having an affair with the brother of her maid. That is when we find out that Libby has known all along about her husband’s affair.
In the season finale, Virginia is shocked to find out that her ex-husband is seeking custody of their children, and he might have a strong case, since she’s a working mother who doesn’t spend enough time at home. In the end, she gives up custody of her kids in the hopes that the documentary will be a hit and her career will profit, but that doesn’t happen. The film is caned and another one is shown instead, one about the rival doctor. That is when we find out that Ethan Hass, Virginia’s ex, has been working for the rival research doctor.
In the final moments of the second season, we see Virginia continuing her work with Masters, after having lost almost everything.