The control of cardiac myocyte growth is a highly regulated, developmentally dependent process. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle soon after birth in mammals. Although the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and whether species-specific differences exist, it appears that the vast majority of adult cardiac myocytes are terminally differentiated. The recent identification of endogenous cardiac stem cells capable of giving rise to cardiac myocyte-like cells may account for some of the previous discrepancies in published studies as to the proliferative potential of cardiac myocytes and challenge the dogma that the heart is a terminally differentiated organ. This chapter will review the recent advances that have been made in identifying candidate factors and signaling pathways that are involved in mediating cardiac cell cycle and proliferation.