Phosphatidylinositols are important in intracellular signaling. In response to extracellular signals, these molecules undergo rapid turnover and generate second messengers including diacylglycerol, inositol 1,4,5-trisphosphate, phosphatidylinositol 3,4-bisphosphate (PtdIns 3,4P2) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns 3,4,5-P3). The importance of phosphoinositide metabolism is underscored by its link to a human genetic disorder oculocerebrorenal syndrome of Lowe in that the gene product (OCRL) deficient in this syndrome is an inositol polyphosphate 5-phosphatase. A new pathway for formation of PtdIns 3,4-P2 and PtdIns 3,4,5-P3 has been found recently. PtdIns 4,5-P2-synthesizing enzymes phosphatidylinositol 4-phosphate 5-kinases (PIP5K) also have kinase activity towards PtdIns 3-P and PtdIns 3,4-P2 forming PtdIns 3,4-P2 and PtdIns 3,4,5-P3 respectively. Surprisingly, they can synthesize PtdIns 3,4,5-P3 directly from PtdIns 3-P in a concerted reaction. PIP5K isozymes may play pivotal roles in intracellular signaling.