It is generally thought that the adult heart has too little endogenous ability to appreciably restore myocardium that is lost after ischemia or infarction. In contrast, the fetal and early neonatal heart have a very high capacity for cardiomyocyte proliferation and regeneration. Why and how the mammalian heart becomes essentially nonregenerative is one of the enduring mysteries of heart biology. Using genetic approaches, my lab has redefined natural heart regeneration as a variable trait subject to the combined influences of multiple polymorphic genes. With this perspective, a number of longstanding questions now become amenable to experimental evaluation. In this presentation, I will discuss genetic, cellular, and mechanistic insights that have been realized based on this new paradigm, and potential therapeutic strategies that could improve endogenous heart regeneration in all patients regardless of their genetic and cellular composition.