Ca2+ is a universal signal: the dynamic changes in its release and entry trigger a plethora of cellular responses. Central to this schema are members of the phospholipase C (PLC) superfamily, which relay information from the activated receptor to downstream signal cascades by production of second-messenger molecules. Recent studies reveal that, in addition to its enzymatic activity, PLC-gamma regulates Ca2+ entry via the formation of an intermolecular lipid-binding domain with canonical transient receptor potential 3 (TRPC3) ion channels. This complex, in turn, controls TRPC3 trafficking and cell-surface expression. Thus, TRPC3 ion channels are functionally linked to both lipase-dependent and -independent activities of PLC-gamma. Understanding the underlying molecular mechanisms that regulate this complex will probably clarify the processes of receptor-activated Ca2+ entry.