The reprogramming of adult cells to a pluripotent state resembling embryonic stem (ES) cells is one of the most exciting advances in stem cell biology in the last decade. These induced pluripotent stem (iPS) cells offer the potential for autologous regenerative therapies, new models to understand disease, and systems for drug discovery. Little is known, however, about the ability of iPS cells to generate cell types of relevance to the cardiovascular system. Two articles1,2 in this issue of Circulation indicate that cardiomyocytes, smooth muscle cells, and multiple types of endothelium can be derived from mouse iPS cells, encouraging efforts toward developing patient-matched cells for cardiovascular disorders. Articles pp 498 and 507 The cloning of Dolly the sheep3 involved reprogramming of an udder cell to a totipotent state by fusion with an enucleated sheep oocyte. Although this breakthrough demonstrated that all mammalian tissues could arise from a single differentiated nucleus, the factors required remained enigmatic. The mechanistic breakthrough came when Takahashi and Yamanaka4 overexpressed a battery of candidate genes in mouse dermal fibroblasts and then grew the cells under conditions favoring expansion of ES cells. They found that ES-like cells emerged, and they systematically winnowed the required list down to 4 transcription factors: Oct4, Sox2, c-myc, and Klf4 (Figure 1). Oct4 and Sox2 are part of the core transcriptional network required for pluripotency. c-myc is a protooncogene required for cell cycle progression. Klf4 is a cell cycle regulator that may control self-renewal of ES cells and block apoptotic pathways induced by c-myc. Recently, reprogramming of human dermal fibroblasts was achieved with the same 4 factors5,6 or with a slightly different cocktail of Oct4, Sox2, Nanog, and Lin28.7 Fortuitously, retrovirally expressed genes typically are silenced in pluripotent cells, meaning that, once established, pluripotency is maintained by endogenous …