Rapid and accurate management of a patient afflicted by cerebral ischemia is crucial for the development of a successful outcome. Yet, it is the understanding of the molecular and clinical presentation of cerebrovascular disease that enables the physician to diagnose and effectively treat cerebral ischemia. Neuronal degeneration can occur at several levels in the ischemic cascade. The free radical nitric oxide (NO) has been clearly linked to ischemic neurodegeneration in both animal models and cell culture systems, but the final cellular pathways that lead from the generation of NO to eventual neuronal death require further investigation. The protective mechanisms of the peptide growth factors basic fibroblast growth factor and epidermal growth factor appear to be linked to the signal transduction pathways of NO, programmed cell death, and protein kinase C. Active modulation of metabotropic glutamate receptor activity also can prevent neuronal injury at or below the level of NO generation. The molecular mechanisms that mediate the protective effects of the metabotropic glutamate receptors are dependent on the modulation of programmed cell death. Further investigation into the molecular signal transduction pathways that are responsible for ischemic neuronal injury will foster the development of efficacious and safe treatments for cerebral ischemia.