Lipids are precisely distributed in the eukaryotic cell where they help to define organelle identity and function, in addition to their structural role. Once synthesized, many lipids must be delivered to other compartments by non-vesicular routes, a process that is undertaken by proteins called Lipid Transfer Proteins (LTPs). OSBP and the closely-related ORP and Osh proteins constitute a major, evolutionarily conserved family of LTPs in eukaryotes. Most of these target one or more subcellular regions, and membrane contact sites in particular, where two organelle membranes are in close proximity. It was initially thought that such proteins were strictly dedicated to sterol sensing or transport. However, over the last decade, numerous studies have revealed that these proteins have many more functions, and we have expanded our understanding of their mechanisms. In particular, many of them are lipid exchangers that exploit PI(4)P or possibly other phosphoinositide gradients to directionally transfer sterol or PS between two compartments. Importantly, these transfer activities are tightly coupled to processes such as lipid metabolism, cellular signalling and vesicular trafficking. This review describes the molecular architecture of OSBP/ORP/Osh proteins, showing how their specific structural features and internal configurations impart unique cellular functions.