Leonard(Johnny Galecki 饰)和Sheldon（Jim Parsons 饰）是一对合起来智商超过360的疯狂科学家宅男。他们的科学家朋友还有风流的Wolowitz（Simon Helberg 饰）和从来不和女人说话的印度人。最近，科学家宅男的对门搬来一个美女剧作家兼餐厅招待，Penny（Kaley Cuoco 饰）。宅男开始蠢蠢欲动了，于是诸多啼笑皆非的故事在几个朋友间“爆炸”开来。

Stepping into the late-late slot vacated by David Letterman, Conan O'Brien stars in a show that far outdoes its competition in sheer strangeness. Along with the celebrity interviews and musical numbers typical of late-night talk shows, this program make frequent use of odd walk-on characters and frequent "visits" from celebrity guests.