Introduction After receiving a diagnosis of congestive heart failure, one in five patients will be dead within 12 months.1 This condition affects at least 10 million people in Western Europe and approximately half this number in the United States, 2 and in 2004, the cost of treating cardiovascular disease and stroke in this country was estimated to reach $368 billion. These statistics alone clearly outline that despite advances in drug and device therapies, new approaches to heart failure are eagerly needed. In this setting, the recognition that endogenous repair mechanisms are inadequate to repair extensively damaged hearts led, more than a decade ago, to testing the concept of repopulating areas of non-viable myocardium with cells. The results of the seminal experiments showing that cells injected into failing hearts could create new tissue and improve function then generated an escalating interest in cell transplantation as a potential new means of treating heart failure. Indeed, the current field of cardiac cell therapy also encompasses acute myocardial infarction and refractory angina in “no-option” patients, but replacement of chronically akinetic scars by new functional myocardium probably remains the most challenging indication because of the limited blood supply to the transplanted cells and the absence of local cues required for driving them towards a cardiomyogenic differentiation pathway.3 The present review focuses on this heart failure setting exclusively. It will summarize the main preclinical data that have established the proof of concept, the results of the initial clinical trials, and the major hurdles that still need to be overcome.