Although several observations over the years suggested a link between the Ras superfamily of GTPases and second messengers generated by the isoforms of phospholipase C, such links had not been substantiated at the molecular level until recently. In particular, identification of a novel phospholipase C isoform, PLC epsilon, which also incorporates domains for guanine nucleotide exchange and Ras binding, have prompted an interest in the interplay between small GTPases and phospholipase C and possible significance of these interconnectivities. Research that followed suggests that activation of each of the major classes of phospholipase C by small GTPases could have a different mechanism and different function, and also that phospholipase C enzymes in turn control Ras GTPases through regulatory proteins that respond directly to second messengers.