Therapeutically controlling inflammation is essential for the clinical management of many high-prevalence human diseases. Drugs that block the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukin-1 (IL-1) can improve outcomes for rheumatoid arthritis and other inflammatory diseases but many patients remain refractory to treatment. Here we explore the need for developing new types of anti-inflammatory drugs and the emergence of novel drug targets based on the clustering of IL-1 receptors into multi-protein aggregates associated with cell adhesions. Interference with receptor aggregation into multi-protein complexes effectively abrogates IL-1 signalling. The exploration of the crucial molecules required for receptor clustering, and therefore signal transduction, offers new targets and scope for anti-inflammatory drug development.