The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system’s primary function in leukocyte migration, it has a central role in immune homeostasis and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity-contributing interactions are attributed to different domains and known to occur in two steps. Here, knowledge on chemokine and receptor domains involved in the first binding-step and the second activation-step is reviewed. A mechanism comprising at least two steps seems consistent; however, several intermediate interactions possibly occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly interact with or rely on transmembrane receptor residues, while CXC-chemokines use residues located further exterior. Moreover, different chemokines for the same receptor often bind at different sites, uncovering the existence of several orthosteric sites thereby adding another level of complexity. This gives rise to a probe-dependency of small molecule “drug-like” ligands, which, depending on the chemokine interaction, may bind allosteric for some, and orthosteric for other chemokines targeting the same receptor, thereby resulting in probedependent pharmacodynamics.