Initial clinical trials of bone-marrow-derived mononuclear cells after acute myocardial infarction have shown improvement in a number of cardiac indices, including left ventricular systolic function, infarct size, stroke volume, and coronary blood flow. Functional improvements observed in cell therapy studies have been modest, with augmentation of left ventricular function in the range of 6-8%. Nevertheless, these studies have generated considerable debate on a number of issues, including the efficacy of specific cell populations, logistics of cell harvesting and isolation, and, most importantly, the mechanism of cell therapy benefit. With the field on the threshold of large-scale, randomized, controlled clinical trials, additional questions, such as the following, must be asked. Can cell therapy procedures be simplified? Can therapeutic effects be obtained earlier after myocardial infarction? Is cell harvesting a necessary component of cell therapy or can endogenous cells be mobilized sufficiently to obviate the need for processing exogenous cells? In an era when interventional devices are increasingly used in therapeutic approaches to acute myocardial infarction, can current cell therapy practice be integrated with interventional approaches to acute revascularization? Emerging concepts that may address some of these questions include whether paracrine factors released by progenitor or stem cells can be as efficacious as bone-marrow- or blood-derived cells, whether novel progenitor populations mobilized locally in the vessel wall or the heart can participate in repair or regeneration, and whether cell therapy strategies for acute myocardial infarction will evolve to include interventional technologies in combination with paracrine or mobilization factors. © 2006 Nature Publishing Group.