Lymphocytes are intrinsically mobile and circulate continuously between the blood and secondary lymphoid tissues. When naive lymphocytes first enter lymph nodes and Peyer's patches, they adhere to and migrate across specific blood vessels known as high endothelial venules (HEVs). The local availability of chemokines in or near HEVs is crucial for the specificity of this process. Here, we summarize recent studies of the chemokine-directed events in lymphocyte trafficking across HEVs, and we examine the dogmas and enigmas concerning lymphocyte migration to lymph nodes and Peyer's patches. A model is also discussed, in which we propose that the response to chemokines immobilized on extracellular-matrix components is important for lymphocyte positioning in vivo.