Season 1

While strolling through the corridors of CalTech, Raj and Leonard notice an ad from a pharmaceutical company seeking patients with extreme shyness to test a new anti-shyness drug. Raj carefully considers registering himself for the advertisement, but after a brief moment decides not to. As the pair stroll past Sheldon's office, they are a little shocked to find that Sheldon has an attractive female visitor. From the following dialogue it quickly becomes apparent that the woman is none other than Sheldon's sister "Missy".

After Sheldon was persuaded by Leonard and Howard, Missy stayed the night at her brother's apartment. Some time later Raj comes to visit too. As the others detect, Raj is miraculously able to talk with woman. Raj confesses that he has signed up as a test subject for the pharmaceutical group from the poster The medication that is being tested claims to combat extreme shyness. To all appearances it is a success. However, the side-effects won't stop; in Raj's case trembling and nervously twitching hands Now Leonard, Howard and even Raj do everything they can to flirt with the beautiful Missy. Which is fine, but after a short time it's too much Luckily Penny pops by and hurries to rescue Missy from all the wooing and takes her with her to get a manicure.

Leonard comes up with an idea. He takes Sheldon aside to talk to him in private. In this private conversation, he tries to convince Sheldon to prevent the whole thing. He drops phrases such as "the man of the house must shoulder the responsibility".

After Sheldon has listened to the whole thing, he decides that none of the three are good enough for his sister. As he announces his decision to his friends, the two women, Penny and Missy, return from the manicures and watch as Sheldon decides the sex life of his sister. Missy is anything but happy about Sheldon's announcement, and would like to have a private conversation with her brother.

In the conversation between the siblings, Sheldon tries to make clear to his sister how important this is for humanity. Since she indeed carries his DNA there was a chance of a little Sheldon being created. Little Sheldons? To be created? Then Missy makes it clear to Sheldon that he cannot in any case decide with whom she sleeps, and that she will injure him "like in their childhood", if he should try again. After Sheldon actually receives a kick he gives up. In spite of this, Missy takes Penny up on her offer and she stays the night at the blonde neighbour's place.

Now that Missy again can to decide who she will go out with for herself, Leonard, Howard and Raj all decide to ask her out on a date. To this end they all take turns visiting the neighbouring appartment Leonard's request for a date was directly rejected. Howard's magic tricks also don't really impress Missy Once Raj was on the list of options, Missy was very happy to see him and asked him why he hadn't asked earlier. But in this moment, coincidentally, the medicine stopped working and no further words came out of his lips...