Ischemic reperfusion injury is a complex pathophysiological event associated with significant impairment of multiple vascular and cellular responses. Oxidative damage due to the presence of radical oxygen species is the essential step that initiates a wide range of intracellular stress signaling processes that culminate in excessive cytokine and chemokine response, adhesion molecule upregulation and nitric oxide overproduction. As we studied all the various mechanisms of injury, we began deciphering the best means to treat the ischemic insult by modulating those proteins or active mediators that are responsible for the lesion. In this manner, we have utilized free radical scavengers, calcium channel blockers, membrane stabilizers, vasodilators, exogenous nitric oxide and arginine, adhesion molecule blockers and small molecule selectin antagonists, in an effort to improve cell function and survival after ischemia and reperfusion. The continuous investigation of new and old compounds that mitigate the ischemic injury will permit us to advance this important field of medicine.