During asymmetric cell division in Drosophila melanogaster neuroblasts, Partner of Inscuteable (PINS) at the apical cortex mediates spindle orientation through two pathways, one of which requires MUD (Mushroom body defect). Wee et al. reveal that the scaffolding protein Canoe (called afadin or AF6 in mammals), which also regulates spindle orientation, does so by directly interacting with PINS and MUD. They show that, in D. melanogaster S2 cells, Canoe binds directly to RAN·GTP; this interaction is important for the localization of MUD to the cortex, where it interacts with PINS to mediate spindle orientation. Canoe also binds the tetratricopeptide (TPR) domain of PINS, which promotes recruitment of Canoe to the cortex, where it can activate the PINS–MUD-mediated spindle orientation pathway. Wee et al. speculate that RAN·GTP may release MUD from importins to allow its interaction with PINS. This mechanism might have broad significance, given that many of these pathway components are conserved in mammals.