Embryonic stem (ES) cells are derived from the blastocyst and have the potential to give rise to derivatives of each germ layer. Induced pluripotent stem (iPS) cells can be derived from lineage-restricted cells, such as fibroblasts and lymphocytes, by forced expression of specific transcription factors. iPS cells are transcriptionally and epigenetically similar to ES cells. Although recent studies indicate that Kruppel-like factors (KLFs) are essential for both maintenance of ES cell self-renewal and reprogramming of somatic cells into a pluripotent state, the molecular mechanism of these processes remains unknown. Thus, understanding the molecular mechanism of ES cell self-renewal and somatic cell reprogramming by Klfs is important for the efficient generation of patient-specific pluripotent stem cells and for the development of regenerative medicine.