Experimental focal ischemia is characterized by a severely ischemic core surrounded by a penumbral zone of more moderately impaired perfusion. Tissue in the core dies of primary energy failure, but secondary events occurring in the penumbra determine whether penumbral tissue will survive or die. These events include rapid elevation of extracellular glutamate and intracellular calcium within neurons, which activates a cascade of degradative enzymatic and oxidative injury. While in the microvasculature, ischemic mediators, including eicosanoids, endothelin-1, free radicals, and proinflammatory cytokines, induce vasoconstriction, heightened vascular permeability, edema formation, and leukocyte adhesion, resulting in microvascular obstruction and secondary ischemic injury. Pharmacologic intervention designed to inhibit some of these key events can successfully reduce ischemic damage.