Amy and Howard begin collaborating on a neuroprosthetics project, upsetting Sheldon and Raj, who feel they are not spending as much time with them. When they seek solace with an annoyed Bernadette, she exploits the situation to trick Sheldon into doing Howard's chores. Penny successfully employs the approaches recommended in one of Bernadette's parenting books to deal with Sheldon, but Leonard believes she is coddling Sheldon too much. Sheldon and Raj resolve the issue of missing their significant others by spending time together.
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.
Although the original pilot was not picked up, its creators were given an opportunity to retool it and produce a second pilot. They brought in the remaining cast and retooled the show to its final format. Katie was replaced by Penny (Kaley Cuoco). The original unaired pilot has never been officially released, but it has circulated on the Internet. On the evolution of the show, Chuck Lorre said, "We did the 'Big Bang Pilot' about two and a half years ago, and it sucked ... but there were two remarkable things that worked perfectly, and that was Johnny and Jim. We rewrote the thing entirely and then we were blessed with Kaley and Simon and Kunal." As to whether the world will ever see the original pilot on a future DVD release, Lorre said, "Wow, that would be something. We will see. Show your failures..."
Campbell and Pemberton start a publicity tour for their Nobel campaign, including appearing on The Ellen DeGeneres Show. Caltech reaches out to previous winners, including George Smoot, Kip Thorne and Frances H. Arnold, only to find that Sheldon has offended most of them in the past. Leonard and Penny convince them to show up to the reception, only for Pemberton and Campbell to crash the party. Leonard holds Sheldon back, only for Amy to verbally snap at them. Meanwhile, with Halley scared of the dark, Stuart and Bernadette turn Howard's story from his time in outer space into the children's book: The Frightened Little Astronaut. Howard is embarrassed until Bernadette talks him into helping children and Stuart's art career by letting it be published.
After Sheldon reminds the guys about the time they mined Bitcoin without him, the guys go on a quest to find their suddenly valuable missing cryptocurrency. They realize the currency is on a laptop which Leonard gave to Penny when they dating, which she then gave to her ex-boyfriend Zack. After Leonard and Penny go to Zack's apartment, he shows them a seven-year-old video that Penny recorded on the laptop soon after she broke up with Leonard. Leonard is touched by the video which shows a drunk Penny lamenting the break-up of her relationship with him.