Phosphoinositide-specific phospholipase C (PLC) enzymes are common signalling components linked to the activation of most cellular receptors. All PLC families are complex, modular, multi-domain proteins and together cover a broad spectrum of regulatory interactions, including direct binding to G protein subunits, small GTPases from Rho and Ras families, receptor and non-receptor tyrosine kinases and lipid components of cellular membranes. Recent structural determinations of PLC components and their complexes with regulatory proteins and direct mechanistic studies, together with earlier work, have provided the foundation to propose molecular mechanisms that stringently regulate PLC activity.