Phosphoinositide-specific phospholipase C (PLC) plays a significant role in transmembrane signaling. In response to extracellular stimuli such as hormones, growth factors and neurotransmitters, PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to generate two secondary messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). At least four families of PLCs have been identified: PLCβ, PLCγ, PLCδ and PLCε. The PLCβ subfamily includes four members, PLCβ1-4. All four members of the subfamily are activated by α- or β-γ-subunits of the heterotrimeric G-proteins.Phosphorylation is one of the key mechanisms that regulates the activity of PLC. Phosphorylation of Ser1105 by PKA or PKC inhibits PLCβ3 activity. Ser537 of PLCβ3 is phosphorylated by CaMKII, and this phosphorylation may contribute to the basal activity of PLCβ3. PLCγ is activated by both receptor and nonreceptor tyrosine kinases.PLCγ forms a complex with EGF and PDGF receptors, which leads to the phosphorylation of PLCγ at Tyr771, 783 and 1245. Phosphorylation by Syk at Tyr783 activates the enzymatic activity of PLCγ1.PLCγ2 is engaged in antigen-dependent signaling in B cells and collagen-dependent signaling in platelets. Phosphorylation by Btk or Lck at Tyr753, 759, 1197 and 1217 is correlated with PLCγ2 activity.