Stem cells have emerged as a next-generation therapy for cardiovascular disease. Initial clinical trials in patients with myocardial infarction document improved cardiac performance after administration of stem cells, translating their regenerative potential from the bench to the bedside. However, the promise of stem cell-based therapy has yet to be fully exploited, in part due to varying degrees of efficacy on follow-up. Contributing to the uncertain outcome is the variable cardiogenic potential of patient-derived stem cells. A strategy mimicking cardiogenic signaling was here formulated to transform mesenchymal stem cells, derived from human bone marrow, into cardiac progenitors. We identified a set of recombinant trophic factors capable of collectively inducing nuclear translocation of cardiac-specific transcription factors, engaging mesenchymal stem cells into cardiopoiesis, and ultimately securing a phenotype with functional excitation-contraction coupling. Maximizing the cardiogenic potential of human mesenchymal stem cells achieves a critical step in optimizing therapeutic translation.