A substantial need exists for new treatments to prevent and treat cardiac dysfunction. In the 1990s, there was great hope for gene therapy in this regard. Since that time, the focus has switched to cell therapy-in particular, therapy-with the aim of inducing myocardial regeneration. Individually, gene and cell therapies still have substantial promise. Ultimately, however, the convergence of both techniques might be necessary to achieve improvements in cardiac function and more successful clinical outcomes in patients with cardiac dysfunction. This approach has already been adopted for treatment of malignancies. Several gene products are currently being studied, including growth factors and chemokines that can modulate the survival and function of cardiac myocytes following an ischemic event and influence remodeling of the left ventricle. However, several issues remain, including the optimization and characterization of cell types, selection of vectors for gene transfer, and identification of appropriate strategies for delivery. Here, we review the potential and need for cell-based gene therapy for the prevention and treatment of cardiac dysfunction and attempt to discuss the unresolved issues.