Predominant tissue damage in ischemia reperfusion injury occurs not during the period of hypoxia-ischemia, but rather after blood flow is restored. At this stage, molecular oxygen is reintroduced to the tissues, generating cytotoxic oxygen-derived free radicals. Thus, although prompt restoration of blood flow is crucial if the tissue/organism is to survive an asphyxial insult, increased blood flow and high oxygen levels are the major determinants of the damage invoked by hypoxia-ischemia. This article presents a review of the pathophysiology of ischemia/reperfusion injury, as well as a discussion of current and potentially new therapeutic options involving antioxidants, free-range scavengers, nitric oxide, NMDA blockers, magnesium, and others.