Cardiomyocyte proliferation and progenitor differentiation are endogenous mechanisms of myocardial development. Cardiomyocytes continue to proliferate in mammals for part of post-natal development. In adult mammals under homeostatic conditions, cardiomyocytes proliferate at an extremely low rate. Because the mechanisms of cardiomyocyte generation provide potential targets for stimulating myocardial regeneration, a deep understanding is required for developing such strategies. We will discuss approaches for examining cardiomyocyte regeneration, review the specific advantages, challenges, and controversies, and recommend approaches for interpretation of results. We will also draw parallels between developmental and regenerative principles of these mechanisms and how they could be targeted for treating heart failure.