While opening their wedding gifts, Sheldon and Amy cannot figure out the purpose of the glass shard Leonard and Penny gave them. They decide it must be a clue to a scavenger hunt to the real gift. They eventually end up in the coffee shop where they first met and find a locket in the lost and found that they think must be the real gift. The glass shard was actually a crystal chakra wand that Raj gave as a gift to Howard and Bernadette, who then re-gifted it to Leonard and Penny, who finally passed it on as a joke. Leonard and Penny find it less funny when they are given a coded thank-you note they have to use to unlock their WiFi. After making out with his employee Denise at Sheldon and Amy's wedding reception, Stuart finally asks Denise out on a date; while preparing for the date, he has a spray-tan accident, but she just finds it funny and still goes out with him. Raj is depressed everyone else has a relationship and asks his father to arrange a marriage.
Mayim Bialik as Amy Farrah Fowler (guest star season 3, starring seasons 4–12):[52] A woman selected by an online dating site as Sheldon's perfect mate.[53] Amy is from Glendale, CA. While she and Sheldon initially share social cluelessness, after befriending Penny and Bernadette she eventually becomes more interested in social and romantic interaction. Her relationship with Sheldon slowly progresses to the point at which Sheldon considers her his girlfriend, eventually they get married. Amy believes she and Penny are best friends, a sentiment that Penny does not initially share. Amy has a Ph.D. in neurobiology.

Sheldon and Amy struggle to choose a best man and maid of honor from their friends. They secretly decide to test and score them, allowing everyone to have an equal shot at either role. Once the gang finds out, none of them apart from Bernadette and Stuart want to be in the wedding. Sheldon settles for Stuart as best man but, once Leonard tells Sheldon that, as the groom, the decision is his alone, he picks Leonard. Amy is set to call Bernadette but, once Penny realizes Amy is her best friend, she immediately pitches herself for the position and Amy enthusiastically chooses her. Amy later makes Penny tell Bernadette the bad news.

When Penny tells Leonard he needs to be more assertive in making decisions for himself, he starts standing up to Sheldon over small things. His confidence makes him want to demand the university support his idea for a plasma physics project. He threatens to quit if the university refuses, alarming both Sheldon and Penny, who consider this to be a risky career move. Sheldon is conflicted on whether or not he is being selfish over Leonard's decision, but Amy suggests that the fact that he is worried over Leonard's motivation proves that he does care about him, which he acknowledges. President Seibert refuses the project, but in order not to lose Leonard, gives him co-leadership over a photon entanglement project, leaving Leonard proud of himself and Penny impressed. Meanwhile, Raj shows Anu his lab, and suggests one possible answer for something he's seen in space might be alien life. When someone mentions this at his observatory presentation, the scientific community starts mocking him as a conspiracy theorist. Raj points out scientists should consider all possibilities when seeking the truth, though this causes people to think he believes in the Loch Ness Monster.
Sheldon and Amy go on their honeymoon to New York City, starting with Legoland New York. Sheldon's insistence on scheduling their marital relations stresses Amy. He says he only does it to remind himself to be intimate with her. They compromise by letting him make a schedule without sharing it with her. Leonard and Penny discover Mr. Larry Fowler (Teller) in Sheldon and Amy's apartment hiding from his wife (Kathy Bates). Leonard notices parallels in his own marriage, which offends Penny. Leonard apologizes, and Penny convinces Mrs. Fowler to give her husband a break. When Mrs. Fowler wants to hang out with her regularly, Penny scares Larry out of the building. Raj instigates a Twitter feud with Neil deGrasse Tyson but is scared off when confronted over the phone. Neil then calls Bill Nye to scare him, too.
After Neil Gaiman tweets about Stuart's comic book store, it becomes very popular, and the crowds upset Sheldon. Stuart hires an assistant manager named Denise and she impresses Sheldon with her comic recommendations. Amy goes to her for information on comics to connect to Sheldon but when she tries to tell him, he says he's talked enough about comics with Denise. The store's popularity causes Stuart to be unable to babysit for Howard and Bernadette's date night. They try to have another at home, but Stuart shows up so they hurriedly go out. Meanwhile, as Raj sets up a telescope, Penny sees a new comet. Raj takes sole credit for the discovery, angering Penny. Leonard tries to defend her but feels sorry for hurting Raj's career. Penny confronts Raj herself and he agrees to share credit after Penny doesn't give in like Leonard.

Laura Spencer as Emily Sweeney (recurring seasons 7–8, 10, starring season 9):[55] A dermatologist at Huntington Hospital. Emily went to Harvard and delights in the macabre and states that she likes her job because she can cut things with knives. Prior to meeting Raj, Emily was set up on a blind date with Howard. After finding Emily's online dating profile, Raj has Amy contact her as his wingman instead. Their relationship becomes exclusive, but Raj later breaks up with Emily when he becomes infatuated with the bartender Claire (Alessandra Torresani).
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.[70] 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.[71] Sheldon and Amy also briefly end their relationship after an argument over which of their fields is superior.[72]

By season seven, Galecki, Parsons, and Cuoco were also receiving 0.25% of the series' back-end money. Before production began on the eighth season, the three plus Helberg and Nayyar, looked to renegotiate new contracts, with Galecki, Parsons, and Cuoco seeking around $1 million per episode, as well as more back-end money.[36] Contracts were signed in the beginning of August 2014, giving the three principal actors an estimated $1 million per episode for three years, with the possibility to extend for a fourth year. The deals also include larger pieces of the show, signing bonuses, production deals, and advances towards the back-end.[37] Helberg and Nayyar were also able to renegotiate their contracts, giving them a per-episode pay in the "mid-six-figure range", up from around $100,000 per episode they each received in years prior. The duo, who were looking to have salary parity with Parsons, Galecki, and Cuoco, signed their contracts after the studio and producers threatened to write the characters out of the series if a deal could not be reached before the start of production on season eight.[38] By season 10, Helberg and Nayyar reached the $1 million per episode parity with Parsons, Galecki, and Cuoco, due to a clause in their deals signed in 2014.[39]
When Mayim Bialik first learned she had to say goodbye to neurobiologist Amy Farrah Fowler, she opened up about the show ending in a blog post, asking, "And now I start to figure out what next. Where will life take me? Where will this career go? What do I want?" Up next she has a voice role in The Inspector Chronicles, a quasi-parody of Doctor Who making the leap from short to feature film. She'll reprise her role as the voice of the Inspector's time machine, known as B.O.O.T.H. Aside from that, she doesn't have any major projects lined up, aside from preparing to not see her close-knit cast the way she'd grown accustomed to. "We'll have to see what our lives look like," she told Us Weekly in early May about the chance they'll remain close. "I mean, we're all going to be on different schedules now; it's very different."
Professor Proton, Sheldon's favorite childhood show, is being rebooted. After unsuccessfully auditioning for the part, he goes to Wil Wheaton for acting tips for his second audition. However, Sheldon is later dismayed when Wil is offered the role instead. Talking it over with Arthur in his dreams, he is still upset to see his idol replaced and considers Wil an enemy again. Meanwhile, Howard gets a vasectomy while Bernadette is on bed rest. Penny offers to take care of Halley for them, but they insult her by expecting her to be irresponsible. Halley ends up saying her first word by calling Penny "Mama."
Simon Helberg as Howard Wolowitz:[45] An aerospace engineer who got his Masters at MIT. Howard is Jewish and lived with his mother, Debbie (Carol Ann Susi). Unlike Sheldon, Leonard, Raj, Bernadette and Amy, Howard does not hold a doctorate. He goes into space, training as an astronaut and serving as a payload specialist. Howard initially fancies himself as a womanizer, but he later starts dating Bernadette, and they get engaged and married. Howard also has a tendency to waste money on toys and argues with Bernadette because of his oddly low income as an engineer and her high income as a pharmaceutical biochemist.
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