Current therapies for heart failure after myocardial infarction are limited and non-curative. Although regenerative approaches are receiving significant attention, clinical efforts that involve transplantation of presumed stem and progenitor cells have largely failed to deliver. Recent studies of endogenous heart regeneration in model organisms, such as zebrafish and neonatal mice, are yielding mechanistic insights into the roles of cardiomyocyte proliferation, resident stem cell niches, neovascularization, the immune system and the extracellular matrix. These findings have revealed novel pathways that could be therapeutically targeted to stimulate repair following myocardial infarction and have provided lessons to guide future efforts towards heart regeneration through cellular reprogramming or cardiomyocyte transplantation.