AIM: In this review, we discuss the regenerative processes in the heart, focusing on non-cardiomyocyte cell populations (fibroblasts, immune cells, and endothelial cells) in zebrafish and mammals. We highlight the role of signaling pathways in heart repair and the potential for therapeutic strategies based on these mechanisms. PURPOSE OF REVIEW: The review examines key molecular and cellular mechanisms in cardiac regeneration, with a focus on fibroblasts, immune modulation, and endothelial function, to identify strategies for enhancing heart repair. RECENT FINDINGS: Recent advancements in characterization of different cell types at the single cell level, along with the discovery of regeneration enhancer elements, have opened new avenues for cardiac regeneration. Targeting the epicardium, along with fibroblast activation, immune modulation, and endothelial signaling, may offer therapeutic strategies to enhance heart regeneration by supporting cardiomyocytes in mice and humans. While non-cardiomyocytes in zebrafish contribute to heart regeneration, in mice and humans, these cells often drive fibrosis instead. Understanding these species-specific differences is crucial for optimizing therapeutic approaches to treat cardiac injury and prevent fibrosis.