Rab proteins are a large family of monomeric GTPases that comprise about 70 members. These proteins cycle from a GDP-bound to a GTP-bound state and are considered molecular switches of membrane traffic. Indeed, they control several steps of vesicular trafficking such as vesicle formation, vesicle movement on actin and tubulin cytoskeletal tracks, vesicle tethering, docking and fusion to the target compartment. Accordingly, Rab proteins are considered key factors in vesicular trafficking as they have a fundamental role in specifying identity and routing of vesicles and organelles. Given their role in membrane traffic, it is not surprising that Rab proteins control the cellular fate of several membrane molecules such as signal transduction receptors and ion channels, being thus fundamental for their correct function. However, much evidence of interaction of a number of Rab proteins with cargo has been reported, raising the question of the functional meaning of these interactions. Indeed, Rab proteins have been demonstrated to directly interact with several membrane proteins, such as signaling receptors, immunoglobulin receptors, integrins and ion channels. Growing evidence indicates that, through interactions with Rab proteins, cargos directly control their own fate. Furthermore, often a cargo protein has the ability to interact with more than one Rab and/or with the same Rab in different activation states. This review focuses on these interactions highlighting their role in modulating cargo's trafficking and functions.