Chemokines control the specificity of lymphocyte homing. Numerous chemokines have been identified but the significance of redundancy in chemokine networks is unexplained. Here we investigated the biological significance of distinct chemokines binding to the same receptor. Among CCR4 ligands, skin vessels endothelial cells present C-C chemokine ligand (CCL) 17 but not CCL22 consistent with CCL17 involvement in T lymphocyte arrest on endothelial cells. However, CCL22 is much more powerful than CCL17 in the induction of rapid integrin-dependent T cell adhesion on VCAM-1 under conditions of physiological flow. The dominance of CCL22 over CCL17 extends to other CCR4-mediated phenomena such as receptor desensitization and internalization and correlates with the peculiar kinetics of CCR4 engagement by the two ligands. A similar phenomenological pattern is also shown for CXC chemokine ligand 9 and CXC chemokine ligand 11, which share binding to CXCR3. Our analysis shows how quantitative variations in chemokine receptor expression level and ligand engagement may alter the selectivity of integrin-dependent lymphocyte adhesive responses, suggesting a mechanism by which chemokine networks may either generate or break the specificity of lymphocyte subset recruitment.