Ion channels are end-targets (effectors) in a large number of regulatory pathways that are initiated by G-protein-coupled neurotransmitters and hormones. Modulation of ion channels by G proteins can be indirect (via second messengers and protein kinases) or direct, via physical interactions between G-protein subunits and the channel protein. These direct physical interactions are the focus of this review. A direct regulation has been firmly established for several voltage-dependent Ca(2+) channels and the G-protein-activated K(+) channels. In these ion-channel families, the G-protein beta gamma subunits (G beta gamma) are the active regulators, whereas the role of the alpha subunits (G alpha) remains poorly understood. Accumulating evidence suggests that intricate relationships between the receptor, G alpha, G beta gamma and the ion channel play a major role in determining the specificity and magnitude of the overall regulation.