Patient-specific pluripotent cells may serve as a limitless source of transplantable tissue to treat a number of human blood and degenerative diseases without causing immune rejection. Recently, isolation of patient-specific induced pluripotent stem (iPS) cells was achieved by transducing fibroblasts with four transcription factors, Oct4, Sox2, Klf4, and c-Myc. However, the use of oncogenes and retrovirus in the current iPS cell establishment protocol raises safety concerns. To generate clinical quality iPS cells, the development of novel reprogramming methods that avoid permanent genetic modification is highly desired. The molecular mechanisms that mediate reprogramming are essentially unknown. We argue that establishment of a stable and self-sustainable ES-specific transcriptional regulatory network is essential for reprogramming. Such a system should include expression of Oct4, Sox2, Nanog and probably other pluripotenty-promoting factors from endogenous loci and establishment of a permissive epigenetic state to maintain such expression. In addition, though not yet proven experimentally, overcoming cellular senescence of fibroblasts by inactivating Rb and p53 pathways and up-regulating telomerase activity may also be required. © 2008 Wiley-Liss, Inc.