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The results of large-scale clinical trials involving granulocyte colony-stimulating factor (G-CSF)-based mobilization of bone marrow stem cells to improve cardiac remodeling and function after acute myocardial infarction have been disappointing. These trials came about as the result of an explosion of animal studies reporting dramatic successes with this therapeutic approach and small-scale nonrandomized, nonblinded clinical trials suggesting beneficial effects in humans as well. It would be rash to conclude, however, that G-CSF-based stem cell therapies for repairing the injured or failing heart are not worth pursuing. Recent advances in basic science not only help explain the failure of the larger clinical trials but have revitalized interest into using G-CSF-based or G-CSF-related therapies for the injured heart. This article will provide an overview of recent advances that have been made in the direct protective actions of G-CSF on cardiac cells, the mobilization of stem cells from the bone marrow, and the delivery of these cells to the heart. Such knowledge could be readily exploited to make G-CSF-based therapy a reality for the clinician.