Phosphatidylinositol transfer protein (PITP) was originally identified and named because of its ability to transport phosphatidylinositol through the aqueous phase from one membrane compartment to another. Recent data, however, indicate unanticipated roles for PITP in the coupling of PIP 2 synthesis to signal transduction reactions and to membrane traffic in mammalian cells. PITP was recently purified on the basis of its ability to restore cellular functions in permeabilized cells depleted of cytosolic proteins. These functions include cell-surface receptorregulated hydrolysis of PIP 2 by phospholipases Cβ€-and β₯-isozymes, regulated release of secretory granules, and the budding of constitutive secretory vesicles and immature secretory granules from the trans-Golgi network. In the yeast Saccharomyces cerevisiae, a PITP was identified from a mutant strain with a defect in the secretory pathway (SEC14) and therefore required for cell viability; in Yarrowia lipolytica, PITP is required for differentiation from a yeast to a mycelial growth form. We are just beginning to unravel the intriguing mechanisms by which PITP/SEC14 may accomplish its function in eukaryotic cells in signal transduction and membrane trafficking.