Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (iPS) cells. It remains unknown if nuclear reprogramming induced by these four factors can globally reset the epigenetic differences between differentiated cells and pluripotent embryonic cells. Here, using novel selection approaches, we have generated iPS cells from fibroblasts to characterize their epigenetic state. Like ES cells, female iPS cells showed reactivation of a somatically silenced X chromosome and underwent random X inactivation upon differentiation. Moreover, genome-wide analysis of two key histone modifications, H3K4 and H3K27 trimethylation, indicated that iPS cells are highly similar to ES cells. Consistent with these observations, iPS cells gave rise to viable high degree chimeras with contribution to the female germ line. Together, these data show that transcription factor-induced reprogramming leads to the global reversion of the somatic cell epigenome into an ES-like state. Our results provide a paradigm for studying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormal epigenetic reprogramming likely does not pose a problem for the potential therapeutic applications of iPS cells.