Approaches to iPS cell generation and the obstacles to their clinical translation. (A) In canonical approach (dark-gray arrow), retroviral derived iPS cells could differentiate into varied cell types. However, the risk of tumor formation and their culture in xeno-medium can inhibit the clinical translation of these cells. Alternative non-integrating approaches[30, 31] in which the overexpression of defined reprograming factors in various ways (green arrowhead) generate iPS cells that circumvent tumor formation, and when cultured in xeno-free medium, can avoid the xeno contamination that hinders their clinical translation. Several bottlenecks, including epigenetic errors, low efficiency, and protocol optimization, are highlighted (blue cylinder). (B) Various cell sources (microscopic images) can be reset for a journey back in time to iPS cells (illustrated as the time machine icon).