Patients with type 2 diabetes (T2D) exhibit chronic activation of the innate immune system in pancreatic islets, in insulin-sensitive tissues, and at sites of diabetic complications. This results from a pathological response to overnutrition and physical inactivity seen in genetically predisposed individuals. Processes mediated by the proinflammatory cytokine interleukin-1 (IL-1) link obesity and dyslipidemia and have implicated IL-1β in T2D and related cardiovascular complications. Epidemiological, molecular, and animal studies have now assigned a central role for IL-1β in driving tissue inflammation during metabolic stress. Proof-of-concept clinical studies have validated IL-1β as a target to improve insulin production and action in patients with T2D. Large ongoing clinical trials will address the potential of IL-1 antagonism to prevent cardiovascular and other related complications.