Oct3/4, Sox2, Klf4, and c-Myc could reprogram mouse fibroblasts to a pluripotent state similar to that of embryonic stem (ES) cells opened major new avenues of research. 1 This epigenetic reprogramming was rapidly extrapolated to the human system using either the same combination of reprogramming factors or a slightly different combination of transgenes (OCT4, NANOG, SOX2, LIN28). 2–4 Like embryonic stem (ES) cells, iPS cells can be used for basic developmental biology research and also as a cell source to generate theoretically unlimited quantities of desired cell types such as cardiomyocytes. Such differentiated cells types can be used in a wide range of basic research studies and potentially in clinical applications, which not only include cellular therapies but also drug discovery and safety testing. One appealing aspect of human iPS cells compared to human ES cells is that they can be more readily generated without specialized expertise and access to human embryos, which also avoids the ethical challenges associated with human embryo research. Potentially the most powerful advantage of iPS cells over ES cells is that they can be generated from any patient to produce genetically identical pluripotent cells that can create human disease models or generate patient-specific cells for therapy. Already a number of iPS cell human disease models have been generated, 5, 6 and proof-of-principle iPS cellular therapies have been pioneered in mouse models. 7–9 Despite the speed at which the iPS cell field is racing forward, we are just at the beginning of a long road. Many major questions remain regarding iPS cells. Will they prove to be equivalent to ES cells in their properties? In other words, will iPS cells be equally as pluripotent as ES cells and readily generate all cell lineages represented in the 3 embryonic germ layers? Will different iPS cell lines show distinct differentiation profiles which may be an advantage or disadvantage for a given application? For example, will certain iPS cell lines be less able to differentiate into cardiovascular relevant cell types compared to other lines? Another critical question for therapeutic applications is whether reprogrammed iPS cell lines are prone to tumorigenesis. Does the starting cell source matter? How does the technique of reprogramming impact iPS cell behavior? In this issue of Circulation Research, Martinez-Fernandez et al address some of these questions by carefully examining the cardiogenic potential of mouse iPS cells generated from murine fibroblasts using 3 reprogramming factors (OCT4, KLF4, and