Lymphocytes recirculate continuously from the blood to organized lymphoid tissues where they are most likely to encounter their cognate antigen. In peripheral lymph nodes (PLN), lymphocytes are thought to leave the blood stream via high endothelial venules (HEV) that express the peripheral node addressin (PNAd) and other specialized molecules for lymphocyte recruitment. We have recently developed a method to study lymphocyte interactions with PLN venules in anesthetized mice. Intravital microscopy analysis revealed that lymphocyte homing to PLN follows a multi-step cascade of molecular interactions : after passing through a dense network of capillaries in the nodal cortex, lymphocytes tether and roll in paracortical venules, especially in HEV, via L-selectin binding to PNAd ; rolling cells are subsequently activated by a lymphocyte-specific stimulus that triggers pertussis toxin-sensitive G proteins ; this induces functional upergulation of LFA-1 which allows the cells to arrest. While this unique adhesion cascade favors the recruitment of L-selectinHi (preferentially naive) lymphocytes, L-selectin- lymphocytes (such as many memory cells) are not entirely excluded from homing to PLN via venules. Circulating activated platelets can deliver immunocompetent lymphocytes to PLN of L-selectin deficient mice and reconstitute lymphocyte homing and peripheral immunity in these animals. This effect is mediated by platelet P-selectin which can bind simultaneously to P-selectin glycoprotein ligand-1 (PSGL-1) on lymphocytes and to PNAd in venules thus allowing platelets to form a cellular bridge which can substitute for L-selectin. In conclusion, the specificity of lymphocyte homing to PLN is determined by a multi-step cascade of adhesion and signaling events between lymphocytes and lymph node venules. This cascade can be fine-tuned in vivo by additional factors such as the occurrence of activated platelets.