The initial observations describing chemokine receptors as a simple system, with a ligand that binds a unique receptor and activates a Gi protein to trigger calcium flux and cell migration, has evolved to a highly complex signaling machinery that facilitates cell adaptation to the environment. The use of new technical approaches that allow precise analysis of protein-protein interactions in living cells is revealing an unanticipated level of complexity among chemokines and chemokine receptors at the cell surface, and supports previous data on allosteric interactions. This complexity reflects a highly regulated system that allows the precise cell allocation to trigger the optimal response. Knowledge of the dynamic interactions of the ligands and receptors, as well as their interplay with other proteins co-expressed by the cell, with lipids that form the cell membrane, with the cellular cytoskeleton, and with downstream signaling machinery will be crucial to define the context-specific signaling triggered by chemokines and to determine how these inflammatory mediators modulate cell responses. Using a natural mutant of CXCR4, responsible of the Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome, a rare, autosomal dominant, primary immunodeficiency disorder we will see how the complexity can affect receptor function and explain the phenotype of this rare immunodeficiency.