Prostaglandins (PGs) and other eicosanoids are members of a large family of lipid mediators (autacoids). In 1978, Lefer and colleagues (Science 200, 52-55 [1978]) reported that prostacyclin reduces the myocardial tissue injury caused by coronary artery occlusion and reperfusion in the cat. Since this discovery, more than 50 papers have reported on the cardioprotective effects of vasodilator PGs, including prostacyclin. The cardioprotective effects of PGs are due in part to (1) a reduction in afterload, (2) an increase in coronary blood flow, (3) the inhibition of platelet function, and (4) the inhibition of the activation and extravasation of polymorphonuclear granulocytes. All of these effects are secondary to the activation of EP (E-type prostanoid)(2)-receptors, which activate G(s)-protein and, hence, adenylate cyclase. In addition, the protection of organs such as the heart by PGs has been attributed to a cytoprotective effect of these agents, the mechanism of which is largely unknown. We recently have discovered that certain E-type PGs, which do not activate EP(2)-receptors, also reduce myocardial infarct size, without causing a fall in blood pressure (EP(2)-receptor-mediated effects). Having provided a brief introduction into the role of eicosanoids in ischaemia-reperfusion injury of the heart, this review focuses on the recent discovery that selective agonists of EP(3)-receptors reduce myocardial infarct size, without causing haemodynamic side effects. The mechanisms of the cardioprotective effects of these agents are discussed, as are the therapeutic implications.