After cardiac injury in mammals, reactivated epicardial-derived cells (EPDCs), such as fibroblasts, contribute to the formation of a fibrotic scar. Adult zebrafish, however, can regenerate their hearts without scarring, through cardiomyocyte proliferation and EPDC-inactivation. The expression of paired related homeobox 1 (Prrx1) correlates with scar-free wound healing, but its role in heart regeneration has been largely unexplored. Now, Jeroen Bakkers and colleagues show that prrx1b-/- mutant zebrafish have reduced cardiomycocyte proliferation and produce larger scars after cryoinjury. Using immunohistochemistry and transgenic reporter lines, the authors show that prrx1 is expressed in epicardial subpopulations after injury and becomes localised to EPDCs at later stages of regeneration. They use single-cell RNA sequencing of sorted epicardial cells to reveal that prrx1b-/- regenerating hearts have more activated fibroblasts than wild types, resulting in increased fibrosis. In addition, Nrg1, which is secreted by EPDCs to stimulate cardiomyocyte proliferation, is almost absent in prrx1b-/- hearts, and the addition of NRG1 protein is sufficient to rescue cardiomyocyte proliferation. Finally, PRRX1 siRNA knockdown reduces NRG1 mRNA and protein in human EDPCs. Taken together, these data indicate that Prxx1b regulates nrg1 expression to induce cardiomyocyte proliferation and prevents scarring in response to cardiac injury.