Even though the vast majority of ion channels are regulated by voltage, extracellular ligands, phosphorylation, intracellular ions, or a combination of these influences, probably only a handful of ion channels are regulated by direct interaction with activated G proteins. Although results from electrophysiological studies of some channels are consistent with the hypothesis of regulation via direct physical interactions with G proteins, strong biochemical evidence for such interactions is still lacking. In most cases, such evidence has been difficult to obtain because ion channels are present at very low abundances in cell membranes, or because the molecular identity of the channel is unknown. The recent cloning of members of the inwardly rectifying K+ channel and voltage-gated Ca2+ channel families should facilitate the rigorous study of the putative interactions between G proteins and ion channels.