Lymphocyte migration is a critical component of a functional immune system. It increases the efficiency of the regional immune responses and disseminates locally induced effector cells to distant inflammatory sites. Central to the migratory process is the ability of lymphocytes to extravasate from the blood by selectively binding to segments of venules lined by high endothelium in lymph nodes and mucosal-associated lymphoid tissues. Recent studies have demonstrated that the specific recognition and adhesion of lymphocytes to high endothelial venules (HEV) is mediated by receptor/ligand systems that are different between lymph nodes (LN) and Peyer's patches (PP). The differential expression of lymphocyte surface receptors accounts for the preferential migration patterns of distinct lymphocyte subsets. More recently, the existence of specialized dermal endothelial cells in cutaneous tumors and inflamed skin that are capable of supporting lymphocyte adherence has been documented. This lymphocyte-endothelial cell interaction is an energy- and calcium-dependent process that involves surface glycoprotein and carbohydrates, requirements that are analogous to lymphocyte binding to HEV in LN and PP. Interestingly, antibodies directed against surface molecules mediating adhesion to HEV of LN and HEV of PP have no effect on lymphocyte binding to the dermal endothelium, suggesting that an additional receptor/ligand system promotes lymphocyte traffic into this site. Moreover, similar but additional receptor/ligand interactions may exist and may mediate lymphocyte migration into other sites. The identification and isolation of these receptor/ligand systems will provide important insights into both regional specialization of the normal immune response and pathophysiology of inflammatory diseases in diverse organs and tissues.