Purpose of Review <p>This review explores current advancements in drug discovery for promoting cardiomyocyte proliferation and highlights key challenges in translating these findings to clinical applications.</p> Recent Findings <p>High-throughput screening platforms, including phenotypic assays using stem cell-derived or neonatal cardiomyocytes, have identified candidate compounds that modulate proliferative signaling pathways. Computational modeling and omics analysis have enabled mechanistic insights and supported the development of targeted drug discovery strategies. Emerging approaches are increasingly incorporating orthogonal screening and cross-species validation to improve translational potential.</p> Summary <p>While no therapy has yet fully translated beyond pre-clinical models, significant progress has been made in identifying candidate drugs that stimulate cardiomyocyte proliferation in animal models. Translating these findings into effective therapies requires a rigorous foundation in basic research to clarify the molecular mechanisms of cardiac repair and guide drug development.</p>