Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. The ability of MSC to differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells, make them an attractive therapeutic tool for heart failure. Recent in vitro and in vivo studies have revealed the underlying mechanisms of MSC in cardiac repair. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of a variety of angiogenic, antiapoptotic, and mitogenic factors. Endogenous MSC as well as exogenously administered MSC have also been suggested to migrate and participate in cardiac repair. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure.