Acetaminophen (paracetamol) has been used therapeutically in Western medicine for about 110 years. Its fever-lowering and pain-relieving properties are well known, even though the specific mechanisms responsible for these actions are still uncertain. Recent and ongoing investigations have revealed previously-unpublished actions of this agent. This review focuses on heart and vasculature. For example, relative to vehicle-treated control hearts, we have found that acetaminophen improves the rate of recovery and the magnitude of ventricular function in the postischemic, reperfused mammalian myocardium. This is true whether the agent is administered before, during, or after ischemia. It is also true of the chronic administration of acetaminophen. Among other possibilities, mechanisms include antioxidation against hydroxyl radicals, hydrogen peroxide, and peroxynitrite (myeloperoxidase is likely to be added to the list in the near future). Acetaminophen also appears to be protective against myocardial infarction and necrosis (manuscript in preparation) as well as against the ventricular dysfunction caused by hypoxia / reoxygenation (manuscript in review). Moreover, it has recently been shown to block the actions of myeloperoxidase, and to attenuate the production of conjugated dienes and oxysterols, all of which are implicated in the pathogenesis of vascular disease. As these and related future results become known, acetaminophen could well be added to the list of preferential therapeutics in the management of heart and vascular disease.