The cytokine network is an essential component of the intercellular communication that controls many key physiological processes in the human body. Cytokine dysfunction underlies multiple pathologies including autoimmune disorders, Alzheimer’s disease and cancer, and runaway overproduction of cytokines can be lethal as is the case for sepsis or flu pandemics. Although the first therapeutic successes with cytokines were obtained with the straight use of selected cytokines such as erythropoietin, most therapies now focus on inhibiting cytokine function. Successes include anti-TNF therapy for arthritis, and promising results were recently also obtained with JAK kinase inhibitors to inhibit cytokine signaling. Yet, many key cytokines including the interferons, tumor necrosis factor and interleukin 1 have important clinical potential, we here mention cancer treatment and vaccine development, but so far have mostly failed in the clinic due to their systemic toxicity. Strategies to selectively overcome these unwanted side effects are the main theme underlying this ERC-CYRE project. We believe that this can be achieved through a better understanding of the mechanisms that determine the specificity of cytokine action at the ligand, receptor and signaling levels.