G protein-coupled receptors remain the single largest group of “druggable” proteins that continue to find tremendous utility in academic lab and pharmaceutical company drug-discovery programs. In 1994, Siderovski was the first to report the sequencing of a “Regulator of G protein Signaling” (RGS protein): 'G0/G1-switch gene-8' or G0S8 (subsequently renamed RGS2). Before the discovery of RGS proteins, the duration of heterotrimeric G-protein signaling was thought to be controlled solely by the intrinsic GTP hydrolysis rate of the G-alpha subunit. What Siderovski originally identified as the G0S8-homology ("GH") domain in proteins from several eukaryotic genomes (human, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae) is now known as the "RGS domain", a 130 amino-acid domain that contacts G-alpha switch regions to stabilize the transition state, thus accelerating GTP hydrolysis (i.e., RGS proteins act as GTPase-accelerating proteins or "GAPs" for G-alpha-GTP). Discovery of a superfamily of RGS domain-containing proteins that negatively regulate G-alpha-dependent signaling resolved a prior paradox that GPCR-stimulated signals are seen to terminate much faster in vivo than predicted from the slow GTP hydrolysis rates exhibited by purified G-alpha subunits in vitro. RGS proteins are now considered key desensitizers of heterotrimeric G protein signaling and, as such, as new drug discovery targets.