ABSTRACT Functional specialization in a multicellular organism arises when cell fate is established by a specific gene expression pattern. During development from a totipotent cell this is accomplished by the synthesis of spatial and signaling cues that result in epigenetic modifications to elicit unipotent gene expression. Once established, such gene expression patterns are stable unless disrupted by disease or injury. Remarkably the over expression of a few proteins can result in reprogramming of an established cell fate to generate induced pluripotent stem cells (iPSCs) that have the potential to develop into any of the cells of an embryo just like embryonic stem cells (ESCs). iPSCs are the ideal starting point for regenerative therapy since they overcome the ethical and practical concerns of using ESCs. Thus reprogramming provides an ideal model system to mechanistically define cell identity safeguards. However a critical barrier to studying reprogramming is the low efficiency (~3%) and differential kinetics (2-3 weeks) of obtaining iPSCs, so that heterogeneous transcriptional changes are masked in population based studies. We have generated a high efficiency system that combines epigenetic and signaling regulators. Using this system, in this proposal we will determine the most parsimonious route of reprogramming to iPSCs and elucidate the chromatin transitions in cells that become reprogrammed.