Although there has been a great amount of progress in the 25 years since the first reporting of the cDNA for IL-1α and IL-1β, the history of IL-1 goes back to the early 1940s. In fact, the entire field of inflammatory cytokines, TLR and the innate immune response can be found in the story of IL-1. This Viewpoint follows the steps from the identification of the fever-inducing activities of “soluble factors” produced by endotoxin-stimulated leukocytes through to the discovery of cryopyrin and the caspase-1 inflammasome and on to the clinical benefits of anti-IL-1β-based therapeutics. It also discusses some of the current controversies regarding the activation of the inflammasome. The future of novel anti-inflammatory agents to combat chronic inflammation is based, in part, on the diseases that are uniquely responsive to anti-IL-1β, which is surely a reason to celebrate the 25th anniversary of the cloning of IL-1α and IL-1β.