Unlocking the regenerative potential of the mammalian neonatal heart is key for the treatment of heart failure in adults, but how and why the ability to regenerate is lost during cardiac maturation is not well understood. Now, Enzo Porrello and colleagues investigate the role of β-catenin, a key effector of the Wnt signalling pathway, to reveal that β-catenin promotes distinct transcriptional programmes in regenerative, immature versus non-regenerative, adult cardiomyocytes. Using RNA-seq and ChIP in human pluripotent stem cell-derived cardiomyocytes, the authors define a Wnt/β-catenin regulatory network that drives proliferation in immature cells. Gain-of-function experiments using a constitutively active β-catenin show that a similar network acts in the neonatal mouse heart. In the adult mouse heart, however, constitutively active β-catenin promotes cardioprotective effects, such as reduced scarring after myocardial infarction. The authors show that, although β-catenin fails to completely re-engage the neonatal proliferation network, β-catenin can partially activate a distinct immature response in adult cardiomyocytes that drives metabolic changes. Altogether, these results provide new insights into the transcriptional regulatory functions of β-catenin in regenerative and non-regenerative cardiomyocytes, and suggests that proliferative factors may switch from regenerative to protective functions during postnatal cardiac maturation.