Phosphatidylinositol transfer proteins (PITPs) have historically been thought to help execute lipid-sorting events by transporting phospholipid monomers between membrane bilayers. Recent data, however, indicate unanticipated roles for PITPs in the coordination and/or coupling of phospholipid metabolism with vesicle trafficking and the downregulation of signal-transduction reactions. We are only now beginning to appreciate both the identities of PITP-dependent cellular reactions and the intriguing mechanisms by which PITPs execute their functions in eukaryotic cells.