The first human trial of stem cell therapy for cardiovascular disease was performed 4 years ago. Since that time, almost a dozen studies have reported the early and late clinical effects of cell therapy in acute myocardial infarction and chronic ischemic cardiomyopathy. Initial nonrandomized trials universally showed slight improvement in the left ventricular ejection fraction. Later randomized, controlled trials, however, suggested a less significant effect. They showed either no difference between cell therapy and control treatment or a slight treatment benefit with cell therapy that is lost by 12 months' follow-up. These results have dampened the enthusiasm of some members of the scientific community for the continuation of clinical trials. Because early phase I trials should not be judged on issues other than safety, however, research is unlikely to be hindered. Indeed, the clinical studies reported so far have already taught us a lot about the biology of myocardial repair. Achieving clinical success will, however, probably require much more investment in basic and experimental research. Here, we address some of the current pitfalls in clinical cell therapy trials and lessons that should be learned as we face the challenges of the future.