Major advances have been made recently concerning mechanisms involved in the generation of second messengers derived from agonist-induced phospholipid metabolism. New functions for well-known GTPases have been described, and other well-characterized proteins have been identified as regulators of phospholipases and phosphokinases. ARF and Rho have been recently identified as activators of phospholipase D. Rho regulates not only phospholipase D but also phosphatidylinositol 4-phosphate 5-kinase. Both beta gamma- and alpha-subunits of heterotrimeric G-proteins have been described as regulators of a new isoform of phosphatidylinositol kinase. Phosphatidylinositol transfer protein is now recognized as an essential requirement for both phospholipase C gamma and C beta isozymes to hydrolyze phosphatidylinositol 4,5-bisphosphate in cells. Some of these proteins such as ARF, Rho, and phosphatidylinositol transfer protein have well-defined roles in vesicular traffic and in cytoskeletal reorganization, thus bringing the field of signal transduction closer to the world of vesicular traffic as well as the cytoskeleton.