Leonard and Sheldon are brilliant physicists—geniuses in the laboratory but socially challenged everywhere else. Enter beautiful, street-smart neighbor Penny, who aims to teach them a thing or two about life. Despite their on-again, off-again relationship in the past, Leonard and Penny have finally gotten married. Even Sheldon has found a female companion, entering into a "relationship agreement" with neurobiologist Amy Farrah Fowler, and he recently took their relationship to the next level by marrying her after a long courtship. In their free time, Leonard and Sheldon enjoy fantasy role-playing games with their ever-expanding universe of friends, including fellow scientists Koothrappali, Wolowitz, and Wolowitz’s adorable microbiologist wife, Bernadette, who is adjusting to life with their two children.
When Bernadette tells Howard that she is expecting again, he is once again floored with fear about raising another child, particularly when he learns it’s a boy. Howard, who isn't athletically inclined, worries he will not be able to relate to a son who might one day expect his dad to be the stereotypical father. Despite his best attempts to get out of it, Howard has a vasectomy to avoid any future surprises and is placed on bed rest, joining his pregnant wife at home.
Sheldon and Amy are surprised to find that Wil Wheaton's new Professor Proton show is actually very entertaining and that Wil had Howard on as a guest. On Howard's suggestion, Sheldon apologizes to Wil, mending their friendship, and tells him he wants to be on the show; but Wil asks for Amy. Sheldon tells her to do it, but she says she often doesn't do things to avoid upsetting him. Sheldon is horrified when he realises how selfish he has been, especially when he finds out that the men do the same for him. Sheldon encourages Amy to go on the show to inspire girls to pursue science while trying to control his obvious jealousy for her. Meanwhile, Leonard writes a book about a physicist that solves a murder, the protagonist Logan Dean is based on himself. Bernadette points out Logan's mean boss Illsa is similar to Penny, who thinks it is based on Bernadette, though Leonard does not correct her. However, Bernadette tells Penny the truth, upsetting her and making her mad at Leonard. After calling his mother for advice, Leonard learns that Illsa is actually like her; but abandons the book when he realizes he wrote romantic tension into the relationship between the characters.