The role of the mitochondrial ATP-sensitive potassium channel (mKATP) in ischemic preconditioning and cardioprotection is reviewed. A great deal of accumulated evidence implicatese opening of this channel as an important step in the anti-infarct effect of ischemic preconditioning. Recent studies, however, reveal that channel opening can actually serve as a signal transduction element. Data indicate that mKATP opening causes mitochondria to generate reactive oxygen species (ROS) which then activate downstream kinases. Opening of mKATP prior to ischemia can serve as a trigger since the critical time for its opening is prior to the onset of the lethal ischemic insult. Most Gi-coupled receptors trigger protection through the mKATP/ROS pathway except for the adenosine receptor which uses some other, as yet unidentified, pathway. Possible coupling schemes between the receptors and the mKATP are discussed. Protection from preconditioning can also be aborted when a mKATP blocker is present only during the lethal ischemic insult (mediator phase), but a much higher concentration of the blocker is required. Thus the mKATP probably serves a dual role as both a trigger and a mediator. Possible end-effectors of preconditioning's protection are discussed including the mKATP itself.