Interleukin-6 (IL-6) is a pivotal cytokine with a diverse repertoire of physiological functions that include regulation of immune cell proliferation and differentiation. Dysregulation of IL-6 signalling is associated with inflammatory and lymphoproliferative disorders such as rheumatoid arthritis and Castleman disease, and several classes of therapeutics have been developed that target components of the IL-6 signalling pathway. So far, monoclonal antibodies against IL-6 or IL-6 receptor (IL-6R) and Janus kinases (JAK) inhibitors have been successfully developed for the treatment of autoimmune diseases such as rheumatoid arthritis. However, clinical trials of agents targeting IL-6 signalling have also raised questions about the diseases and patient populations for which such agents have an appropriate benefit-risk profile. Knowledge from clinical trials and advances in our understanding of the complexities of IL-6 signalling, including the potential to target an IL-6 trans-signalling pathway, are now indicating novel opportunities for therapeutic intervention. In this Review, we overview the roles of IL-6 in health and disease and analyse progress with several approaches of inhibiting IL-6-signalling, with the aim of illuminating when and how to apply IL-6 blockade.