The production of cardiomyocytes is required both for embryonic heart formation and for cardiac regeneration following injury. The transcription factor Hand2 has been implicated in cardiomyocyte formation, but now, Deborah Yelon and colleagues demonstrate that Hand2 can in fact drive cardiomyocyte production in zebrafish (p. 3112). They show that the overexpression of hand2 in early zebrafish embryos enhances the proliferation of cardiac progenitors within the second heart field, leading to increased numbers of cardiomyocytes and hence an increase in heart size. This cardiac enlargement also results from an increase in cardiomyocyte specification within the first heart field. Furthermore, they report, these effects require the phosphorylation-independent dimerization of Hand2 but not its direct binding to DNA. The researchers further investigate the role of Hand2 during regeneration and demonstrate that, in line with its role during development, hand2 overexpression can boost cardiomyocyte production following injury. These findings implicate the induction of hand2 expression as a key component of the cardiac regenerative response in zebrafish. Given that HAND2 has also been implicated in congenital heart disease (CHD) in humans, these findings also provide novel insights into the origins of CHD.