The notion that it takes two to tango is certainly true for leukocyte transendothelial migration. A growing pallet of leukocyte adhesion-induced signaling events in endothelial cells have been identified, mediating both short-term (i.e. permeability) as well as long-term (i.e. regulation of transcription) effects. Efficient paracellular migration (i.e. through endothelial cell–cell junctions) requires both intracellular calcium and the actin cytoskeleton, but also involves small GTPases, reactive oxygen species and protein kinases. The alternative route of transcellular migration appears to depend on components such as caveolae and intermediate filaments. This minireview discusses our current knowledge on the regulation of leukocyte transmigration through endothelial signalling.