The cytokine interleukin (IL)-6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL-6 receives considerable attention in studies of innate and adaptive immunity, the IL-6-related family member IL-27 is increasingly recognized for its effects on cellular proliferation, differentiation and leukocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells where they direct the transition from innate to adaptive immunity. However, they are frequently identified as lymphokines that control responses in T cells and B cells. In this regard, IL-27 often opposes the action of IL-6. Here, we will review the role of IL-6 and IL-27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease. This article is protected by copyright. All rights reserved.