During inflammation, coordinated expression of cytokine-induced adhesion molecules (CAMs) on postcapillary venular endothelial cells (ECs) regulates leukocyte recruitment. During their recruitment from blood, leukocytes adhere to EC CAMs, activating signaling pathways inside ECs. In a forthcoming paradigm, leukocyte transendothelial migration requires active EC participation, with extracellular adhesive CAM functions mirrored by cytoplasmic do-main-dependent intracellular events. These events serve to reorganize the EC actin cytoskeleton. Investigators have visualized this as changes in EC shape, transient opening of EC-EC contacts, and redistribution of CAMs expressed on the luminal EC surface. In this review, we (1) summarize the overlapping extracellular adhesive properties of the 3 EC CAMs most important for leukocyte recruitment during inflammation, namely, E-selectin, vascular cell adhesion molecule, and intercellular adhesion molecule-1; (2) explore the role of these 3 CAMs as signal transducers by identifying the intracellular signals (Ca++, Rho/Rac, and phosphatidylinositol 4,5-bisphosphate) that upon leukocyte engagement, reorganize the EC cytoskeleton and redistribute these apical CAMs, thereby favoring leukocyte recruitment; and (3) describe how CAM-derived signals lead to ezrin-radixin-moesin complex formation and how this complex of plasma membrane-cytoskeleton adapter proteins coordinates CAM-driven intracellular signals with extracellular adhesive CAM functions. This literature review suggests that the cytoplasmic domains of these EC CAMs and their downstream effectors represent new and potentially beneficial intracellular therapeutic targets for treating diseases of the skin.