Sudden cardiac death is a euphemism for ventricular fibrillation (VF) in the majority of cases of ischemic heart disease. It occurs most commonly during acute (<1 h duration) ischemia. There is a hierarchy of mechanisms that includes electrophysiological dysfunction and the accumulation or depletion of local cardiac biochemicals (mediators). Unfortunately, there are many biochemicals that accumulate or are depleted during ischemia and infarction, so it is not yet clear which are the true mediators. Candidates include potassium, catecholamines, histamine, serotonin, lysophos-phatidylcholine, palmitylcarnitine, platelet activating factor, prostaglandins, leukotrienes, thromboxane A₂, angiotensin-II, endothelin, opioids, protons, and thrombin. Mediators may elicit arrhythmias by acting in series (one biochemical or the effects of its depletion determining the arrhythmogenicity of another) or in parallel (biochemicals or their depletion operating independently to cause ventricular arrhythmias). It remains to be determined whether a series or parallel model best decribes arrhythmogenesis during acute ischemia. A better understanding of the relative importance of individual mediators, and the manner in which their effects interact would greatly assist drug development for prevention of VF.