Stem cells are believed to be important for regeneration of several adult tissues. Recently, adult stem cells with very broad differentiation potential have been identified although whether they represent vestigial primitive pluripotent stem cells or products of extremely rare de-differentiation events involving tissue-specific stem cells is not known. Transdifferentiation of tissue-specific stem cells across lineage boundaries has also been demonstrated but the relative inefficiency of the process in vivo, even in the presence of tissue damage, questions whether such a mechanism is of physiologic relevance. Interestingly, among adult stem cells, the capacity for lineage switching appears to be greatest in stem cells that can be cultured ex vivo for extended periods. If the normal cell fate decisions of diverse adult stem cell types could be reliably redirected at high frequency in situ, possible regenerative therapies for a wide variety of diseases could be envisioned. An integrated understanding of the transcriptional regulatory networks that comprise the various adult stem cell entities as well as the signaling pathways governing their differentiation into therapeutically useful cell types will facilitate clinical application of these exciting findings.