Nearly two decades of research in regenerative medicine have been focused on the development of stem cells as a therapeutic option for treatment of the ischemic heart. Given the ability of stem cells to regenerate the damaged tissue, stem-cell-based therapy is an ideal approach for cardiovascular disorders. Preclinical studies in experimental animal models and clinical trials to determine the safety and efficacy of stem cell therapy have produced encouraging results that promise angiomyogenic repair of the ischemically damaged heart. Despite these promising results, stem cell therapy is still confronted with issues ranging from uncertainty about the as-yet-undetermined "ideal" donor cell type to the nonoptimized cell delivery strategies to harness optimal clinical benefits. Moreover, these lacunae have significantly hampered the progress of the heart cell therapy approach from bench to bedside for routine clinical applications. Massive death of donor cells in the infarcted myocardium during acute phase postengraftment is one of the areas of prime concern, which immensely lowers the efficacy of the procedure. An overview of the published data relevant to stem cell therapy is provided here and the various strategies that have been adopted to develop and optimize the protocols to enhance donor stem cell survival posttransplantation are discussed, with special focus on the preconditioning approach.