Transport factors in the karyopherin-β (also called importin-β) family mediate the movement of macromolecules in nuclear-cytoplasmic transport pathways. Karyopherin-β2 (transportin) binds a cognate import substrate and targets it to the nuclear pore complex. In the nucleus, RaṅGTP binds karyopherin-β2 and dissociates the substrate. Here we present the 3.0Å structure of the karyopherin-β2-RaṅGppNHp complex where GppNHp is a non-hydrolysable GTP analogue. Karyopherin-β2 contains eighteen HEAT repeats arranged into two continuous orthogonal arches. Ran is clamped in the amino-terminal arch and substrate-binding activity is mapped to the carboxy-terminal arch. A large loop in HEAT repeat 7 spans both arches. Interactions of the loop with Ran and the C-terminal arch implicate it in GTPase-mediated dissociation of the import-substrate. RaṅGppNHp in the complex shows extensive structural rearrangement, compared to RaṅGDP, in regions contacting karyopherin-β2. This provides a structural basis for the specificity of the karyopherin-β family for the GTP-bound state of Ran, as well as a rationale for interactions of the karyopherin-Ran complex with the regulatory proteins ranGAP, ranGEF and ranBP1.