Cardiovascular diseases (CVDs) are a major cause of mortality and morbidity worldwide for more than half of century despite significant advances in treatment. Therefore, we still need for novel therapeutic options. Cell therapy has recently become an alternative therapy for CVDs. This review is devoted to current therapeutic strategies based on stem cells in cardiology. We discuss some challenges arising in stem cell therapy and propose approaches that could increase efficacy of cell therapy for cardiac diseases. We focus on some new insights onto the mechanisms regulating stem cell function highlighting the role of microenvironment in maintaining stem cell viability and regenerative potential after transplantation. Cell sheets and cell patches are considered as a new generational cell-based regenerative therapy. We discuss the prospects of stem cell secretome and extracellular vesicles (exosomes) as “cell therapy without the cells” and development of cardiac regenerative medicine using human IPSC-derived cardiomyocytes and direct reprogramming.