In addition to their role in energy transduction, mitochondria play important non-canonical roles in cell pathophysiology, several of which utilize the mitochondrial ATP-sensitive K(+) channel (mitoK(ATP)). In the normal heart, mitoK(ATP) regulates energy transfer through its regulation of intermembrane space volume and is accordingly essential for the inotropic response during periods of high workload. In the ischemic heart, mitoK(ATP) is the point of convergence of protective signaling pathways and mediates inhibition of the mitochondrial permeability transition, and thus necrosis. In this review, we outline the experimental evidence that support these roles for mitoK(ATP) in health and disease, as well as our hypothesis for the mechanism by which complex cardioprotective signals that originate at plasma membrane receptors traverse the cytosol to reach mitochondria and activate mitoK(ATP).