The identification of AGS proteins as receptor-independent activators of G-protein signaling reveals unexpected mechanisms for the regulation of heterotrimeric G-protein activation and has opened up new areas of research related to the role of G proteins as signal transducers. In addition to their obvious interest associated with G-protein-coupled receptor signaling, AGS proteins might provide alternative binding partners for G-protein subunits that enable them to serve unexpected functions related to cell division, differentiation and organelle structure that might operate independently of a GPCR. Thus, these proteins and the concepts advanced with their discovery highlight the diversity associated with G-protein signaling and present new avenues for the development of therapeutics that target G-protein signaling.