Stem cell therapy appears to be a promising area of research for cardiac regeneration following ischemic heart failure. However, in vitro differentiation of cardiomyocytes from pluripotent stem cells, or directly from somatic cells, leads to generation of "immature" cardiomyocytes that differ from their adult counterparts in various ways. This immaturity triggers some challenges for their potential clinical use, and multiple techniques reviewed here have been developed for in vitro maturation of those cells. Nevertheless, full maturity of cardiomyocytes remains elusive and will remain the main challenge for stem cell therapy in the near future.