The ATP-sensitive potassium channel (KATP) has been shown to serve an endogenous cardioprotective role in a number of experimental models of myocardial stunning and infarction. More importantly, a majority of evidence has also been obtained which suggests that the KATP channel may be intimately involved in both triggering and maintaining the cardioprotection afforded by the phenomenon of ischemic preconditioning particularly in large animal models such as dogs and pigs. Although the evidence for an involvement of KATP in ischemic pre-conditioning is equivocal in smaller animal species such as rabbits and rats, activation of this channel by KATP channel openers produces cardioprotection in all species studied. Whether this channel is an important mediator of ischemic preconditioning in all animal species including man and the mechanism by which this cardioprotective effect is obtained await further experimental studies. Nevertheless, the use of selective potassium channel openers to mimic preconditioning in selected clinical settings may be a desirable future therapeutic goal.