The G-protein-mediated signaling system has evolved as one of the most widely used transmembrane signaling mechanisms in eukaryotic organisms. Mammalian cells express many G-protein-coupled receptors as well as several types of heterotrimeric G-proteins and effectors. This review focuses on recent data from studies in mutant mice, which have elucidated some of the roles of G-protein-mediated signaling in physiology and pathophysiology.