Phospholipase C (PLC) activity exerts effects on both vascular smooth muscle (VSM) contractility and growth. Conventional wisdom tells us that serpentine receptor agonists stimulate PLCβ through the pertusis toxin-insensitive heterotrimeric G-protein G_q or through βγ subunits, whereas growth factors stimulate PLCγ activity through tyrosine phosphorylation. However, accumulating data now suggests that PLCβ isoforms are rarely expressed in VSM, and that the profile of PLC isoforms expressed is dependent on the state of differentiation, with PLCδ being a major constituent of contractile VSM. PLCδ is probably the earliest isoform of PLC in evolutionary terms although its role and regulation remains obscure. Intriguingly both PLCδ and PLCγ have recently been shown to be regulated by various GTP-binding proteins. Consequently past assumptions regarding the contribution of individual PLC isoforms in VSM signaling should be re-evaluated.