Ischemia and reperfusion (I/R) are thought to play an important role in the pathophysiology of ischemic diseases of the heart. It is now well appreciated that leukocyte–endothelial cell interactions are important determinants for I/R-induced microvascular injury and dysfunction. There is a growing body of experimental data to suggest that reactive metabolites of oxygen and nitrogen are important physiological modulators of leukocyte–endothelial cell interactions. A number of investigators have demonstrated that I/R enhances oxidant production within the microcirculation resulting in increases in leukocyte adhesion and transendothelial cell migration. Several other studies have shown that exogenous nitric oxide (NO) donors may attenuate leukocyte and platelet adhesion and/or aggregation in a number of different inflammatory conditions including I/R. The objective of this review is to discuss the physiological chemistry of reactive metabolites of oxygen and nitrogen with special attention given to those interactions that may modulate leukocyte–endothelial cell interactions, provide an overview of the evidence implicating reactive metabolites of oxygen and nitrogen as modulators of leukocyte–endothelial cell interactions in vivo, and discuss how these mechanisms may be involved in the pathophysiology of ischemic heart disease.