Since their discovery 13 years ago, chemokines have emerged as the most important regulators of leukocyte trafficking. On target cells, chemokines bind to seven-transmembrane-domain receptors that are coupled to heterotrimeric Gi proteins. The common response of all cells to chemokine stimulation is chemotaxis. In addition, leukocyte activation triggers diverse signal transduction cascades; which cascade is triggered depends on the chemokine and receptor engaged. The selective activation of distinct pathways suggests that the receptors couple not only to G proteins but also to additional downstream effectors. This review discusses recent advances in the elucidation of the signal transduction that occurs in proximity to receptors and that leads to the early biochemical events in leukocyte activation.