The proliferative capacity of mammalian cardiomyocytes diminishes shortly after birth. In contrast, adult zebrafish and neonatal mice can regenerate cardiac tissues, highlighting new potential therapeutic avenues. Different factors have been found to promote cardiomyocyte proliferation in zebrafish and neonatal mice; these include maintenance of mononuclear and diploid cardiomyocytes and upregulation of the proto-oncogene c-Myc. The growth factor NRG-1 controls cell proliferation and interacts with the Hippo–Yap pathway to modulate regeneration. Key components of the extracellular matrix such as Agrin are also crucial for cardiac regeneration. Novel therapies explored in this review, include intramyocardial injection of Agrin or zebrafish-ECM and NRG-1 administration. These therapies may induce regeneration in patients and should be further explored.