Recently, a series of exciting reports have revealed that terminally differentiated somatic cells can be reprogrammed to generate induced pluripotent stem (iPS) cells via overexpression of a cocktail of transcription factors such as Oct3, Sox2, Klf4, and c-Myc or Oct3, Sox2, Nanog, and Lin28. Most recently, these iPS cells has been used to generate viable, live-born progeny by tetraploid complementation. Reprogramming of iPS cells inaugurates a new era of biology and medicine, it inevitably brings new challenges, e.g., how these factors induce reprogramming and how their expression is regulated. To facilitate iPS cell research, this review focuses on how expression and activation of these transcription factors are regulated.