During receptor-mediated endocytosis, ligand-bound receptors are internalized into clathrin-coated endocytic vesicles; these are then rapidly uncoated, before undergoing a series of fission events that segregate the ligand (which is destined for degradation) from the receptor (which is recycled). Clathrin uncoating is relatively well understood, but we know much less about the fission process. Alan Wolkoff and co-workers have therefore screened for proteins that might control fission, using an in vitro system that reconstitutes microtubule-based motility and fission of early endocytic vesicles containing the ligand asialoorosomucoid (see p. 2749). They find that the small GTPase Rab4 and the kinesin motor KIF2C are associated with ligand-containing vesicles. Furthermore, they show that addition of GST-conjugated Rab4-GTP inhibits motility and vesicle fission; preincubation with the non-hydrolysable GTP analogue GTP-γ-S has a similar effect. GDP, by contrast, increases the extent of vesicle trafficking and fission. The authors conclude that Rab4 serves as a molecular switch in endocytic vesicle fission. They propose that hydrolysis of GTP bound to Rab4 triggers kinesin-driven movement of the vesicles along microtubules, which results in vesicle fission and consequently ligand/receptor segregation.