AbstractIL‐37 is a unique member of the IL‐1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. Immune and non‐immune cells produce IL‐37 precursor following pro‐inflammatory stimuli. Following activating cleavage by caspase‐1, mature IL‐37 translocates to the nucleus, where it suppresses transcription of pro‐inflammatory genes. Both precursor and mature IL‐37 are also secreted in the extracellular space, where they bind IL‐18Rα and recruit the IL‐1R8 (formerly TIR8 or SIGIRR), which transduces anti‐inflammatory signals by suppressing NF‐kB and MAPK and by activating Mer‐PTEN‐DOK pathways. During inflammation, IL‐37 restores the metabolism of the cell by reducing succinate, inhibiting mTOR, and activating AMPK. Transgenic mice expressing human IL‐37 and wild type mice treated with recombinant human IL‐37 are protected from several experimental models of inflammation, including endotoxin shock, colitis, lung and spinal cord injury, coronary artery disease, arthritis and inflammation‐induced fatigue, while also exhibiting reduced adaptive immune responses. In humans, IL‐37 likely functions to limit excessive inflammation: accordingly, IL‐37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the discovery and biology of IL‐37, and discuss the potential for development of this cytokine as a therapeutic agent.