Heart failure is a growing epidemic caused by cardiomyocyte depletion. Current therapies prolong survival by protecting remaining cardiomyocytes but are unable to overcome the fundamental problem of regenerating lost cardiomyocytes. Several strategies for promoting heart regeneration have emerged from decades of intensive study. Although some of these strategies remain confined to basic research, others are beginning to be tested in humans. We review strategies for cardiac regeneration and summarize progress of related clinical trials.