Heart disease is one of the largest causes of death in humans throughout the developed world. Despite its critical role in maintaining physiologic homeostasis, the adult mammalian heart does not exhibit a significant capacity for regeneration. By contrast, several lower vertebrates exhibit a remarkable ability to regenerate the aging myocardium in response to severe injury. Additionally, recent evidence has shed light on a transient regenerative window in postnatal mammals. In this review, we discuss key findings that help to unravel the differences in cardiac regeneration across phylogeny and ontogeny. Furthermore, we highlight recent significant progress in the pursuit of adult mammalian cardiac regeneration. Collectively, this important body of work has great potential impact on human therapy for heart failure.