Acute myocardial infarction remains to be one of the most important problems of health care. Cardiac cell therapy is a new therapeutic strategy focused on repair of the injured cardiac muscle. Mesenchymal stem cells (MSC) are considered as the most suitable candidates for cardiac cell therapy. MSC transplantation in the myocardium after ischemic injury has been shown to be cardioprotective in animal models and clinical trials. However, the beneficial effects of MSC in humans are limited because of both poor survival and impaired function of the cells in ischemic tissue. To address these issues, a number of approaches to the modification of MSCs with the aim to improve their survival and proliferation, reduce the immune reaction, enhance transdifferentiation, and optimize the profile of secreted paracrine factors have been tested. In this review, we provide detailed discussion of different methods of MSCs modification, including targeted gene overexpression, conditioning of MSCs using physical and chemical factors, and application of multicellular units for transplantation. The effectiveness of these strategies in preclinical studies is also discussed.