Despite advances in clinical management, cardiovascular disease remains the leading cause of death in America. While cardiomyocytes retain limited plasticity following maturation, the heart is grossly unable to recover from structural damage. Mesenchymal stem cell (MSC) therapy, through its promise of repair and regeneration of cardiac tissue, represents an exciting avenue of treatment for a range of cardiovascular diseases. MSCs are relatively immunoprivileged, lacking both major histocompatibility II and T-cell co-stimulatory signal expression, and possess the unique ability to home into sites of myocardial damage when delivered systemically. Additionally, they have been shown to provide therapeutic benefit via several distinct mechanisms, the most important of which appears to be the abundant secretion of paracrine factors that promote local regeneration. In light of this, several groups have sought to precondition MSCs, using various molecular and genetic means, in order to enhance viability and growth factor secretion in the heart, following transplantation. Here, we analyze and integrate information from recent MSC studies, focusing on underlying mechanisms of MSC-associated repair in animal models of cardiac disease. Additionally, MSC pretreatment studies are organized here to examine their relative effectiveness and potential for clinical use. Data emerging from ongoing human clinical trials are also evaluated for consistency with animal studies and their therapeutic promise. Finally, we attempt to answer whether cumulative evidence from animal and human studies is suggestive of significant, clinically viable cardiac repair in acute and chronic conditions and explore ways in which future studies can enhance effectiveness of cell-based therapy.