Hypoxia in the ischemic region during an acute coronary syndrome leads to release of the nucleotide AMP. T cell–produced CD73 hydrolyzes this nucleotide to adenosine, which in turn engages the A2bR, which is predominantly expressed in the ischemic myocardium by cardiac fibroblasts. The cardiac fibroblasts respond by releasing IL-6. IL-1, also activated within the ischemic region, can impinge on cardiomyocytes, endothelial cells, and smooth muscle cells, as well as on resident macrophages, to augment local IL-6 production. IL-6 and IL-1 can mediate fever, a common concomitant of acute coronary syndromes. IL-6 can also stimulate hematopoiesis, contributing to the leukocytosis that can accompany acute coronary syndromes. Additionally, IL-6 can activate leukocytes and adipose tissue to augment local and systemic inflammation. In hepatocytes, IL-6 unleashes the acute-phase response, heightening the production of fibrinogen, the precursor of thrombi, and of plasminogen activator 1 (PAI-1), which inhibits endogenous fibrinolysis. A role for cardiac fibroblasts in producing IL-6 and orchestrating an inflammatory response during acute coronary syndrome extends our understanding of the complex circuits of inflammatory signaling following myocardial ischemic injury.