The formation of the mammalian neocortex relies on the migration of projection neurons into specific layers, which is in turn regulated by cyclin-dependent kinase 5 (Cdk5). Cdk5 has previously been shown to interact with the G protein-coupled receptor serotonin 6 receptor (5-HT6R); however, whether and how this interaction might be important for neocortical migration remains unclear. Now, on p. 3370, Alexandre Dayer and colleagues use a range of knockdown and rescue in utero electroporation experiments in mouse to show that 5-HT6R regulates the migration of the upper layer cortical projection neurons via its interaction with Cdk5, rather than with serotonin or other agonists. Knockdown of 5-HT6R in postmitotic upper layer neurons impairs their migration and leads to their presence in deeper layers of the neocortex, while re-expression of the full-length receptor or a Cdk5 kinase rescues this defect. The interaction between Cdk5 and 5-HT6R specifically affects the transition between multipolar and bipolar morphology in immature migrating neurons and provides in vivo evidence for the role of a G protein-coupled receptor in neocortical neuron migration.