Inositol lipids have specialized functions in eukaryotic organisms. Not only do they provide a source of second messengers but they are also recognized as signaling molecules. Moreover, inositol lipids are required as substrates for PLC and PI3K activities, as well as having a role in cytoskeletal reorganization and vesicular traffic. The cytosolic protein Phosphatidylinositoltransfer protein (PITP) is a key regulator of the cellular mechanism that can compartmentalize the synthesis of these phosphoinositides. PIPTs mediate the transfer of monomeric phosphatidylinositol (PI) or phosphatidylcholine (PC) molecules between two membrane compartments of a cell. Sec14p is a PIPT found in yeast, and is the prototype for a protein module called the SEC14 domain. SEC14 domains are found in proteins from plants, yeast, invertebrates, and mammals (named CRAL_TRIO domain), suggesting an ancient evolutionary origin. Many proteins with a SEC14 domain consist only of this module, while others are larger proteins with additional protein–protein interaction or catalytic domains. It appears likely that the SEC14-only proteins are bona fide lipid transport proteins, while the multi-domain SEC14-containing proteins have more complex functions in signal transduction, transport, and organelle biology, where they integrate lipid metabolism with other biochemical processes. Abberant functioning of SEC14, either due to individual deficiencies, genetic mutations or chemical inhibition, impairs cell viability through compromised Phosphatidylinositol (PtdIns) trafficking through the trans-Golgi network (TGN) and endosomal systems, phosphatidylserine decarboxylation to phosphatidylethanolamine, fatty acid metabolism, polarized growth, and fungal dimorphism. Mutations in PITPs, or PITP-like proteins, are also root causes of mammalian neurodegenerative and lipid homeostatic diseases.