SignificanceGPCRs are major mediators of transmembrane signal transduction, responding to a wide range of stimuli including hormones and neurotransmitters. Important targets of GPCR signaling,PLCβenzymes catalyze the hydrolysis ofPIP2intoIP3andDAG, leading to increased intracellular Ca2+levels and activation of PKC, respectively.PLCβs exhibit very low basal activity through multiple mechanisms of autoinhibition and are activated by bothGαqandGβγ. In this study, we demonstrate thatGβγactivatesPLCβby recruiting it to the membrane where its substratePIP2resides and by orienting its active site. This activation mechanism permits robust and rapid activation ofPLCβupon GPCR stimulation in the setting of low background activity during GPCR quiescence.