The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 mediates recruitment of mononuclear cells, modulates monocyte and lymphocyte phenotype and regulates fibrous tissue deposition and angiogenesis. MCP-1 is markedly induced in the infarcted myocardium and plays an important role in infarct healing and post-infarction remodeling. MCP-1 null mice exhibit decreased macrophage recruitment in the infarcted heart, delayed phagocytosis of dead cardiomyocytes, diminished fibroblast infiltration and attenuated left ventricular remodeling. Targeted deletion of CCR2, the primary MCP-1 receptor also protects from the development of adverse remodeling following myocardial infarction. In addition to its role in infarct healing, MCP-1 signaling plays an important role in the development of interstitial fibrosis in a mouse model of brief repetitive myocardial ischemia and reperfusion. Our review manuscript discusses the mechanisms responsible for MCP-1-mediated effects in the ischemic myocardium and explores MCP-1 targeting as a novel therapeutic approach in patients with myocardial infarction and ischemic non-infarctive cardiomyopathy.