Abstract Leukocyte extravasation is a multistep process characterized by rolling and arrest on the endothelium followed by transendothelial migration (TEM). Arrest and TEM by T cells typically requires the activities of chemokines and their receptors. Previously, we showed that CCR2 identifies highly differentiated, readily activated CD4+ memory T cells in human blood with diverse effector capabilities, and we showed that CCR6 is the signature chemokine receptor for Th17 cells. Here we describe studies of the migratory capabilities and effector profiles of CD4+ CCR6+ CCR2+ as compared with CD4+ CCR6+ CCR2− and CD4+ CCR6− CCR2− T cells from human blood. Using flow chamber assays with TNFa-activated human umbilical vein endothelial cells, we found that among the CCR6+ cells, only the CCR2+ subset was able to cross the endothelial monolayer efficiently. Using antibodies against the CCR6 ligand, CCL20, and a specific inhibitor of CCR2, we found that CCR6 was important for arrest and that CCR2 was critical for subsequent TEM. Using intracellular staining of cells activated ex vivo, we found that although IL-17-expressing cells were found within all CCR6+ subsets, the CCR6+CCR2+ cells were distinguished by their production of IFNg, GM-CSF, and TNFa, thereby demonstrating the cytokine profile of pathogenic Th17 cells as identified in mouse models of autoimmune disease. Taken together, our studies suggest that chemokine receptors on memory Th cells play non-redundant roles in the egress from blood, that providing T cells with CCR6 and CCR2 could enhance their trafficking into tissue, and that, on the other hand, blocking CCR2 alone could prevent the extravasation of pathogenic Th17 cells and ameliorate tissue damage in Th17-cell driven disease.