Pluripotency is governed by the intricate interplay between genetic and epigenetic factors. Previous studies implicate Oct4, Sox2 and Nanog as core regulators of the transcriptional circuitry in pluripotent cells. The three transcriptional factors and their downstream target genes coordinately promote self-renewal and pluripotency. Significant inroads have also been made into elucidating the epigenetic mechanisms governing the exit from a self-renewal state. The recent success in reprogramming both mouse and human fibroblast cells into a pluripotent state has marked a new era in stem cell research and is pertinent to a comprehensive understanding of pluripotency. Reprogramming can be initiated by the introduction of few defined factors. However, the molecular mechanisms driving reprogramming remain largely obscure and await further investigations. Here, we explore the molecular framework governing pluripotency in the context of pluripotent ES cells and the reprogrammed iPS cells.