Chemokine receptors are widely expressed on a variety of immune cells and play a crucial role in normal physiology as well as in inflammatory and infectious diseases. The existence of 23 chemokine receptors and 48 chemokine ligands guarantees a tight control and fine-tuning of the immune system. Here, we discuss the multiple regulatory mechanisms of chemokine signalling at a systemic, cellular, and molecular level. In particular, we focus on the impact of biased signalling at the receptor level; an emerging concept in molecular pharmacology. An improved understanding of these mechanisms may provide a framework for more effective drug discovery and development at a target class that is so relevant for immune function.