The maintenance of immune surveillance and the generation of normal immune responses are dependent on leukocyte migration to appropriate lymphoid and non-lymphoid tissues. The process of leukocyte migration occurs through complex and highly regulated interactions between the circulating leukocytes and the vascular endothelium. Multiple families of adhesion molecules as well as specific chemoattractants and their cognate receptors function to stabilize these interactions and induce migration into the tissue. L-selectin is a key adhesion molecule that regulates both the migration of leukocytes at sites of inflammation and the recirculation of lymphocytes between blood and lymphoid tissues. L-selectin-mediated lymphocyte recirculation is required for maintaining the appropriate tissue distribution of lymphocyte subpopulations including naïve and effector subsets such as regulatory T cells. In addition, L-selectin-mediated entry into peripheral lymph nodes is required for optimal induction of lymphocyte homeostatic proliferation during lymphopenia. Importantly, L-selectin has been shown to have both adhesive and signaling functions during leukocyte migration. Specifically, L-selectin is highly efficient at capturing free-flowing leukocytes from the blood and supporting subsequent fast rolling interactions along the vascular endothelium. During rolling, synergistic interactions between L-selectin and integrin functions slow leukocyte rolling velocities allowing for chemoattractant-induced activation and eventual firm adhesion of the leukocyte to the vascular endothelium. Engagement of L-selectin by ligand generates transmembrane signals leading to activation of intracellular signaling pathways, increased integrin binding affinity, and enhanced chemotaxis. L-selectin has also been shown to mediate leukocyte recruitment during chronic inflammatory and autoimmune diseases and thus is a potential therapeutic target for drug development.