The role of adenosine triphosphate (ATP)-sensitive potassium channels (K+ATP channels) under physiologic and pathophysiologic conditions has been debated in recent years. Moreover, because of the reported pro-arrhythmic effects of potassium-channel openers in the setting of acute myocardial ischemia, the potential benefit of K+ATP-channel modulation in clinical practice has been questioned. Such pro-arrhythmic potential, based on the ability of potassium-channel openers to exacerbate the ischemia-induced shortening of the action potential, is also disputed. Both pro- and antiarrhythmic effects of K+ATP-channel openers (and blockers) have been described. These apparently conflicting results can (to a great extent) be explained by taking into account the electrophysiologic mechanism of a particular arrhythmia. In addition, under ischemic conditions other factors of importance for the development of arrhythmias may, when they are not controlled, determine the outcome. It is concluded that both in normoxia and in ischemia, pharmacologic opening of K+ATP channels might facilitate ventricular arrhythmias when it leads to serious electrophysiologic inhomogeneity. Because such favorable conditions are created only by relatively high doses, the problem of pro-arrhythmogeneity may be overestimated. On the other hand, before widescale application in the treatment of ischemic heart disease is established, well designed clinical and experimental studies should be performed to determine the risk for pro-arrhythmogeneity.