Heart failure is associated with a high rate of morbidity and mortality. In some patients, current treatment modalities may not be adequate to prevent myocardial remodeling, which leads to exacerbation of the disease. Cell therapy is based on the premise of replacing damaged myocardium with functional tissues. Multiple forms of stem cells, including bone marrow-derived stem cells and skeletal myoblasts, have been investigated using several delivery routes of administration. Different mechanisms have been proposed to explain the beneficial effects of cell-based therapy. These include cell transdifferentiation, cell fusion, and release of paracrine growth factors. The beneficial effects of cell therapy may involve multiple mechanisms. The encouraging results of early clinical cell therapy studies have not been sustained by subsequent robust studies. These findings suggest that many unanswered questions need to be addressed before cell therapy becomes an acceptable adjunctive treatment for heart failure.