The consequences of cardiac ischemia–reperfusion are not limited to myocytes but also extend to the coronary endothelium, where they are characterized by decreased nitric oxide (NO)-dependent relaxations. Given the essential role of the endothelium and NO in the regulation of vascular tone as well as platelet and leukocyte function, protection of coronary endothelial cells is an important therapeutic target. In this context, several studies have shown that both early and delayed preconditioning may prevent endothelial dysfunction after index ischemia–reperfusion. This endothelial protection most likely results from the inhibitory effects of preconditioning on expression of endothelial adhesion molecules, resulting in reduced neutrophil–endothelial interactions. The mechanisms of early endothelial preconditioning resemble those described at the level of the myocytes, and may involve mediators such as adenosine, bradykinin, NO and free radicals, together with activation of protein kinase C and opening of ATP-sensitive potassium channels. With regard to delayed preconditioning, recent studies have shown that both NO and free radicals are involved as triggers of this second window of endothelial protection. The complex interactions between these two radical species ultimately lead to a delayed increase in NO production, most likely responsible for the decreased adhesion of neutrophils to endothelial cells. Further identification of the triggers and mediators of this endothelial protection will allow the development of new therapeutic agents targeting both the myocardium and the coronary vasculature.