A variety of ligands, including intracellular nucleotides, pharmaceutical products, and neurohormones, influence the adenosine triphosphate (ATP)-sensitive potassium channel of cardiac muscle. In this review it is emphasized that these ligands act not only on the channel-gating mechanism but also influence each others' effects or effectiveness in a quite complex series of interactions. Thus, ATP, which directly closes the channelgating mechanism, also enhances the efficacy of sulfonylurea drugs and is necessary for the action of certain potassium-channel-opening drugs and neurohormones. Intracellular nucleoside diphosphates that, depending on the conditions, either act on the channelgating mechanism or influence the effectiveness of ATP, also facilitate and reduce the effectiveness of potassium-channel opening and sulfonylurea drugs, respectively. Our knowledge of the mechanisms that underlie the interactions between these different ligands is limited. The cloning of the channel and the characterization of the different ligand-binding sites will be a great step forward.