There is considerable evidence that opening the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) is cardioprotective in ischemia-reperfusion. Two prominent questions surround the role of mitoK(ATP) in the cardiomyocyte: How does opening mitoK(ATP) protect? What is the normal physiological role of mitoK(ATP) in the heart? Before these questions can be addressed, it is necessary to agree on the bioenergetic consequences of opening mitoK(ATP), and this distills down to a single question--does opening mitoK(ATP) cause significant uncoupling or not? The evidence strongly indicates that it does not and that reports of uncoupling and inhibition of Ca2+ uptake are the result of using toxic concentrations of K(ATP) channel openers. Thus, opening mitoK(ATP) results in increased K+ flux that is sufficient to change mitochondrial volume but is insufficient to cause significant depolarization of membrane potential. The volume changes, however, have significant bioenergetic consequences for energy coupling in the cell.