Although most cardiac cell therapy trials have focused on patients with acute myocardial infarction, attempts at "regenerating" chronically failing hearts have also been performed. These studies have entailed use of skeletal myoblasts and bone marrow-derived cells. In the case of skeletal myoblasts, the randomized placebo-controlled myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial has failed to show that myoblast injections increased ejection fraction beyond that seen in controls but the finding that the highest dose of myoblasts resulted in a significant antiremodeling effect compared with the placebo group provides an encouraging signal. In the case of bone marrow cells, surgical injections of the mononuclear fraction combined with coronary artery bypass surgery have not shown a substantial benefit but positive results have been reported with intraoperative epicardial injections of CD133+ progenitors. There are three possible reasons for these mixed results. The first is the marked heterogeneity of cell functionality (particularly in the case of bone marrow), which would expectedly translate into variable clinical outcomes. The second reason is the low rate of sustained engraftment. The third possible explanation is a mismatch between the choice of end points and the presumed mechanism of action of the cells. The initial assumption that adult stem cells could effect myocardial tissue regeneration has led to usual focus on ejection fraction as the major surrogate endpoint. It is now increasingly recognized that adult stem cells, in contrast to their embryonic counterparts, have little if any regenerative capacity and that their presumed beneficial effects more likely involve paracrine signaling, in which case infarct size, perfusion, or left ventricular volumes might be more appropriate markers. Altogether, these observations provide a framework for future research, the results of which will then have to be integrated in the protocol design of second-generation clinical trials. © 2008 Elsevier Inc. All rights reserved.