The existence in mitochondria of separate, highly regulated pathways for K+ influx and efflux strongly implies that mitochondrial volume is subject to regulation in vivo. Volume, in turn has been shown to regulate activity of the electron transport chain. Thus, the mitochondrial K+ cycle appears to play a key signalling role in regulating cellular bioenergetics, including the metabolic fate of fatty acids. Consistent with this role, the channel is inhibited by long-chain acyl-CoA esters and activated by GTP, and these ligands interact with sites that face the cytosol. The work to be summarized shows that KATP channels from mitochondria and plasma membranes are regulated by the same biochemical and pharmacological ligands. We hypothesize that the mitochondrial KATP channel, like its counterparts in the plasma membrane, is heteromultimeric, consisting of a regulatory sulfonylurea receptor (mitoSUR) and an inward-rectifying K+ channel (mitoKIR).