The neonatal capacity for cardiac regeneration in mice is well studied and has been used to develop many potential strategies for adult cardiac regenerative repair following injury. However, translating these findings from rodents to designing regenerative therapeutics for adult human heart disease remains elusive. Large mammals including pigs, dogs, and sheep are widely used as animal models of humans in preclinical trials of new cardiac drugs and devices. However, very little is known about the fundamental cardiac cell biology and the timing of postnatal cardiac events that influence cardiomyocyte proliferation in these animals. There is emerging evidence that external physiological and environmental cues could be the key to understanding cardiomyocyte proliferative behavior. In this review, we survey available literature on postnatal development in various large mammal models to offer a perspective on the physiological and cellular characteristics that could be regulating cardiomyocyte proliferation. Similarities and differences between developmental milestones, cardiomyocyte maturational events, as well as environmental cues regulating cardiac development, are discussed for various large mammals, with a focus on postnatal cardiac regenerative potential and translatability to the human heart.