Intercellular communication mediated by cytokines is the main mechanism by which cells of the immune system talk to each other. Many aspects of cytokine signalling in the immune system have been explored in great detail at the structural, biophysical, biochemical and cellular levels. However, a systematic understanding of the quantitative rules that govern cytokine-mediated cell-to-cell communication is still lacking. Here, we discuss recent efforts in the field of systems immunology to bring about a quantitative understanding of cytokine-mediated communication between leukocytes and to provide novel insights into the orchestration of immune responses and inflammation. Recent advances in systems immunology are beginning to elucidate the quantitative rules that govern cytokine-mediated cell-to-cell communication. This Review describes how combining theoretical analysis with experimental validation can lead to a better understanding of cytokine-mediated communication between cells of the immune system.