Unlike the adult mammalian heart, the adult zebrafish heart is able to regenerate lost muscle tissue following injury. The epicardial sheet covering the heart is required for this regeneration but the genes that underlie epicardial cell responses to injury are unclear. Here, Jingli Cao and co-workers examine gene expression signatures in zebrafish epicardial cells (p. 232). Using single-cell transcriptome sequencing, the researchers reveal that adult epicardial cells are heterogeneous but exist as at least three main populations, as revealed by hierarchical cluster analyses. The analysis of these populations reveals genes that are expressed in a subset-specific manner as well as pan-epicardial genes, some of which represent novel epicardial markers. The authors further report that caveolin 1 (cav1), which encodes a scaffolding protein that is the main component of caveoli, is expressed pan-epicardially and is required for heart muscle regeneration; although cav1 knockout zebrafish exhibit normal heart development, they display severe defects in injury-induced cardiomyocyte proliferation and heart regeneration. Together, these findings provide key insights into epicardial biology and reveal novel regulators of heart regeneration.