Pluripotency and self-renewal are the defining traits of embryonic stem cells (ESCs) and this status quo is maintained by the core transcription factors Oct4, Sox2, and Nanog. Genome-wide mapping of the binding sites of these pivotal factors and other ESC transcriptional regulators has unraveled the transcriptional network governing pluripotency. Strikingly, a sizeable fraction of the binding sites of Oct4 and Nanog are not conserved in mouse and human ESCs. Binding site turnover and the presence of species-specific transposable elements are some of the factors contributing to this disp arity. Hence, comparing human and mouse ESCs will shed new light on the design of transcriptional regulatory networks for pluripotency. Despite the significant differences among pluripotent mammalian stem cells, the same set of transcription factors (Oct4, Sox2, Klf4, and c-Myc) can be used to reprogram human and mouse somatic cells into induced pluripotent stem cells. Recent works also demonstrate that there are multiple ways of imparting pluripotency. For instance, the nuclear receptors Nr5a2 and Esrrb can, respectively, substitute for Oct4 and Klf4 in reprogramming. This chapter summarizes the different roles of transcription factors in the modulation of pluripotent states and in the induction of pluripotent phenotypes.