Cytokines are involved in a wide range of functions shaping the normal immune response, yet inflammatory changes in the immune system due to dysregulated cytokine signaling may lead to the induction of autoimmunity. Cytokine inhibitors have revolutionized the treatment of many autoimmune diseases in recent years. Systemic cytokine ablation, however, is often associated with the development of adverse side effects and some patients simply do not respond to therapy. TNF, IL-1 and IL-6 are the best characterized proinflammatory cytokines considered as the main therapeutic targets for the treatment of several autoimmune and inflammatory diseases. But can anti-cytokine therapy become more selective and thus more efficient? This mini-review discusses several recently emerging paradigms and summarizes current experimental attempts to validate them in mouse studies.