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In 1956, former nightclub singer and single mother Virginia Johnson becomes the assistant to renowned OBGYN William Masters. They embark on their pioneering study in human sexuality while trying to navigate their personal feelings for each other. Masters' wife Libby tries to conceive a child to save her marriage. Dr. Ethan Haas chafes under the supervision of Dr. Masters and deals with a changing society. University Provost Barton Scully struggles to support his protege William Masters while dealing with a long-held personal secret.

Dr. William Masters and Virginia Johnson struggle to get their work back on track while taking their relationship to a much more intimate place. Libby flounders in a loveless marriage and turns to volunteering. Former prostitute Betty DiMello tries for the American dream and ends up working with Masters and Johnson. Dr. Austin Langham becomes the spokesman for a popular diet company and the boy toy to its aggressive founder.

Welcome to the swinging sixties. Thrust into the spotlight by the publication of their controversial study, Dr. William Masters and Virginia Johnson find themselves the unlikely leaders of the sexual revolution. But as newfound fame and pressures mount, their relationship becomes twisted and tangled – putting the couple in a position that even they might not be able to handle.