The idea of growing human cells in vitro to yield a renewable source of cells for transplantation has captured the imagination of scientists for many years. The derivation of human embryonic stem cells (hESC) represented a major milestone in achieving this goal. hESC are pluripotent and can proliferate in vitro indefinitely, rendering them an ideal source for cell replacement therapy. Moreover, recent advances in reprogramming somatic cells into induced pluripotent stem cells (iPS cells) have enabled us to unravel some of the key master regulators of stem cell pluripotency. By integrating recent findings of molecular mechanism involved in maintenance of these different pluripotent stem cell types, we aim to present a global picture of how extracellular signals, intracellular signal transduction pathways and transcriptional networks cooperate together to determine the cell fate of pluripotent stem cells. Unraveling the signaling networks that control stem cell pluripotency will be helpful in deriving novel methods to maintain these pluripotent stem cells in vitro.