Despite declining mortality from cardiovascular diseases, the prevalence of heart failure continues to increase and is itself associated with increasing morbidity, mortality and economic burden to the United States population. Myocardial regeneration is a new therapeutic option for advanced heart failure, which has demonstrated rational progression from initial translational studies to current phase 2 clinical trials. Stem cells are cells that can continuously self-renew and undergo differentiation. Stem cell therapy attempts to augment the inadequate endogenous regenerative capacity of the heart, and to prevent the maladaptive sequelae of myocardial diseases. A number of stem cell types have been evaluated in clinical studies and include skeletal myoblasts, bone marrow derived stem cells, cardiac stem cells, pluripotent stem cells and adipose derived stem cells. A variety of stem cell delivery methods have also been evaluated which include intravenous, intracoronary and intramyocardial transplantation. In this chapter we will review some of the key pre-clinical and clinical trials in both ischemic and non-ischemic cardiomyopathy, focusing particularly on safety, heterogeneity in cell types and delivery methods, and clinical endpoints.