Cosmologist Stephen Hawking made a short guest appearance in the fifth-season episode; in the eighth season, Hawking video conferences with Sheldon and Leonard, and makes another appearance in the 200th episode. In the fifth and sixth seasons, NASA astronaut Michael J. Massimino played himself multiple times in the role of Howard's fellow astronaut. Bill Nye appeared in the seventh and twelfth seasons.
The show originally centered on five characters living in Pasadena, California: Leonard Hofstadter and Sheldon Cooper, both physicists at Caltech, who share an apartment; Penny, a waitress and aspiring actress who lives across the hall; and Leonard and Sheldon's similarly geeky and socially awkward friends and co-workers, aerospace engineer Howard Wolowitz and astrophysicist Raj Koothrappali. Over time, supporting characters were promoted to starring roles, including neuroscientist Amy Farrah Fowler, microbiologist Bernadette Rostenkowski, physicist Leslie Winkle and comic book store owner Stuart Bloom.
Science has also interfered with the characters' romantic lives. Leslie breaks up with Leonard when he sides with Sheldon in his support for string theory rather than loop quantum gravity. When Leonard joins Sheldon, Raj, and Howard on a three-month Arctic research trip, it separates Leonard and Penny at a time when their relationship is budding. When Bernadette takes an interest in Leonard's work, it makes both Penny and Howard envious and results in Howard confronting Leonard, and Penny asking Sheldon to teach her physics. Sheldon and Amy also briefly end their relationship after an argument over which of their fields is superior.
On March 16, 2014, a Lego Ideas project portraying the living room scene in Lego style with the main cast as mini-figures reached 10,000 supporters on the platform, which qualified it to be considered as an official set by the Lego Ideas review board. On November 7, 2014, Lego Ideas approved the design and began refining it. The set was released in August 2015, with an exclusive pre-sale taking place at the San Diego Comic-Con International.
The episode opens with a short montage of clips from the series' twelve seasons, then segues to Sheldon and Amy, who are up late waiting for a call from the Nobel Committee. Following a prank call from Kripke, they are told they've won the Nobel Prize in Physics for their super-asymmetry work. The attention from the media and the university bothers Sheldon. Amy is saddened by an unflattering picture of her in a news report, so Raj convinces her to get a makeover. She loves her new look but Sheldon demands she change it back. Leonard calls him out for being rude, but Sheldon flees when he sees Penny emerge from the newly repaired elevator. Sheldon and Penny go to the Cheesecake Factory and Penny tells Sheldon that change is the only constant thing in life. On a TV, they see Bernadette and Howard take credit as Sheldon and Amy's best friends. Raj and Leonard defend Amy, with Leonard accidentally breaking Sheldon's DNA molecule model in Apartment 4A. Penny convinces Sheldon to ride in the elevator.
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.