Chemokines exert their effects through their interaction with seven transmembrane domain receptors coupled to G-proteins, GPCRs. Such receptor ligation leads to the regulation of numerous activities where chemokines play a key role, including hematopoiesis, T-cell activation, angiogenesis, inflammatory diseases or HIV-1 infection. Here we discuss the molecular mechanisms that underlie chemokine receptor activation. As occurs with other GPCRs, chemokines initiate the signaling cascades by inducing receptor dimerization. This dimerization enables the activation of the JAK/STAT pathway which allows the subsequent triggering of G-protein dependent signaling events. This mechanism provides a new context to explain some of the activities exerted by chemokines and introduces new targets for the development of drugs to fight those diseases were chemokines are implicated, such as inflammation and AIDS.