Endogenous adenosine is produced by the heart during ischemia-reperfusion as a natural cardioprotectant. The benefits of this local protective mechanism can be harnessed by ischemic preconditioning and amplified by drugs such as acadesine, that augment extracellular adenosine levels specifically during an ischemic event. Classically, adenosine production by cardiomyocytes, and measured in the interstitial fluid, is considered the relevant source of this mediator. In contrast, it is proposed that there are two independent sites of adenosine formation in the heart—the myocytes and the endothelial cells, that are differentially regulated. Recent evidence implicates the vascular endothelium as a potentially important site of both adenosine formation and action that subserves the cardioprotective effects of the nucleoside. The mechanisms by which endogenous adenosine protects the heart from ischemia-reperfusion injury require clarification, and may involve different adenosine receptors (A1. A2. and A3) acting through various second messenger systems that contribute to the overall response. Additional studies are required to define the source of adenosine, the mechanisms by which its levels are regulated, and the effector pathways responsible for the myocardial protection observed.