The phospholipase C (PLC) isozymes catalyze conversion of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) into the Ca2+-mobilizing second messenger inositol 1,4,5-trisphosphate (inositol (1,4,5)P3) and the protein kinase-activating second messenger diacylglycerol (DAG).1 Many PLC-dependent cellular responses occur in addition to those mediated by these classical second messengers since the activities of a broad range of membrane, cytosolic, and cytoskeletal proteins are regulated by PtdIns(4,5)P2 binding.2–4 Mammals express 13 different PLCs (Figure 1), which differ markedly in their modes of upstream regulation and physiological functions.5 Many growth factors, antigens, and other extracellular stimuli signal through tyrosine phosphorylation of the PLC-γ isozymes, whereas an even larger group of hormones, neurotransmitters, chemoattractant and chemosensory molecules, and other extracellular stimuli promote physiological effects through heterotrimeric G protein-dependent activation of the PLC-β isozymes. These and other forms of receptor-promoted signaling pathways also communicate to Ras superfamily GTPases, which in turn directly activate certain PLC isoyzmes. Thus, PLC-dependent signal transduction provides one of the major fabrics for communication of cells, and delineation of its function at all levels from the intact animal to the atomic resolution of mechanism is fundamental to understanding mammalian biology. Figure 1 Conserved domain structure of the mammalian PLC isozymes. The 13 functional human PLC isozymes were aligned on the basis of the conservation of the protein sequence, and a dendrogram was constructed to cluster similar sequences into shared branches. The ... Many excellent reviews on PLC-dependent signaling are available that focus, for example, on early aspects of the discovery and function of receptor-promoted formation of Ins(1,4,5)P3/diacylglycerol and mobilization of Ca2+,1,6,7 classification and regulation of the PLC isozymes,8–10 tyrosine phosphorylation-dependent activation,11,12 activation through Ras superfamily GTPases,5,13,14 physiology,15,16 and structure/function.17–19 We have limited this review to a general introduction of the domain and structural features of the PLC isozymes and then consider in detail recent advances made in understanding the mechanisms through which Gα-subunits of the Gq family bind to and activate PLC-β isozymes and how the PLC-β isozymes in turn promote inactivation of this signaling complex by stimulating GTP hydrolysis by the GTP-activated G protein.