The migration of leukocytes across the endothelial lining of the vascular wall requires a complicated series of adhesion and signaling events. Endothelial Ig-like cell adhesion molecules (IgCAMs) such as intercellular adhesion molecule-1 play an important role, not only as ligands for leukocyte integrins, but also as signaling initiators. Clustering these IgCAMs triggers a wide range of events in the endothelial cells’ interior, of which activation of Rho-like GTPases, induction of cytoskeletal changes, and the transient modulation of cell-cell contact are key events. This review discusses recent insights into this IgCAM-driven endothelial signaling and its consequences for leukocyte transendothelial migration.