Membrane trafficking is critical for cell compartmentation which allows the maintenance of specialised environments required for specific cellular activities. To achieve this goal, cells need to tightly regulate vesicle transport between donor and acceptor compartments. Several different protein families are involved: among them the SNAREs (65 genes) and the small GTPases Rabs (57 genes) show the highest number of isoforms and will be in the spotlight. We will focus on the roles of these proteins in the ER–Golgi–plasma membrane pathway to illustrate how Rabs and SNAREs are involved to achieve specific set of functions.