Purpose of review: The last few years have witnessed a growing interest in regenerative therapy of the failing heart by cell transplantation. Special emphasis has been put on skeletal myoblasts and bone marrow-derived stem cells, with a flurry of experimental studies generating overall positive but occasionally conflicting results. It is thus appropriate to review the most important of these studies in light of the major issues that still impede widespread clinical use of cell therapy. Recent findings: Recent laboratory data demonstrate the ability of autologous skeletal myoblasts to engraft into scarred myocardium and improve its function. Equally successful results have been reported with bone marrow-derived cells which, in contrast to myoblasts, are credited with a plasticity that might allow their transdifferentiation into cardiac or endothelial cells in response to organ-specific cues. However, some major questions remain unanswered; they include the choice of the optimal cell type in relation with the target patient population, the strategies for enhancing cell survival and functional integration, the clarification of the mechanisms of improvement, and the means of reducing invasiveness of cell delivery. Summary: Although laboratory research attempts to overcome these persisting hurdles, the accumulated body of evidence warrants implementation of clinical trials. The earliest ones have now documented the feasibility of cell therapy. It is now appropriate to conduct safety and efficacy studies which, if carefully done, should allow assessment of the extent to which this concept of regenerative therapy can be made a clinical reality. © 2004 Lippincott Williams & Wilkins.