Autologous cell therapy with bone marrow (BM)—derived proangiogenic cells is a promising new treatment modality to enhance ischemic recovery after myocardial infarction. However, its introduction into the clinical mainstream is hampered by technical challenges with cell procurement, handling, selection, expansion, and application. In this issue of Circulation , Jujo et al1 show that mobilization of endogenous cells by a clinically approved drug inhibiting the CXC-chemokine receptor 4 (CXCR4) improves myocardial recovery after infarction in a mouse model of ischemia/reperfusion. Article see p 63 The key finding of this study is that a single dose of the highly specific and short-acting CXCR4 antagonist AMD3100 (AMD), a bicyclam also known as plerixafor, reduces early infarct size and adverse cardiac remodeling when administered immediately at the time of reperfusion after coronary ligation. Interestingly, experiments in BM chimeric mice revealed that the protective effect of AMD treatment required endothelial nitric oxide synthase (eNOS) expression in BM but not in peripheral tissues because mice reconstituted with eNOS-deficient BM did not benefit from AMD treatment, whereas eNOS-knockout mice reconstituted with wild-type BM showed a reduction in infarct size and fibrosis. AMD treatment increased baseline and ischemic levels of circulating CXCR4+ and Sca-1+/Flk1+ mononuclear cells compared with control injection and enhanced recruitment of Tie2+ BM-derived cells to the ischemic myocardium, whereas levels of Tie2+ cells decreased in BM. AMD treatment also increased BM eNOS expression, possibly by directly increasing eNOS promoter activity, upregulated BM matrix metalloproteinase-9, and enhanced processing of soluble kit ligand, a key hematopoietic growth factor pathway regulated by NO. Notably, although AMD was administered just once after the induction of ischemia, the biological effects on cell mobilization and growth factor pathway regulation were sustained over several days and required eNOS expression in BM cells. CXCR4 mediates retention and mobilization …