<p>Inflammation has a fundamental role in many disorders of the gastrointestinal tract and the liver. Why these organs are particularly prone to acute, but especially chronic, immune-mediated disorders remains unclear; however, the complex exposure to environmental triggers, including the gut microbiota, might be particularly relevant. Cytokines are considered key regulators of inflammatory processes, with IL-1β being one of the first cytokines discovered, more than four decades ago. A whole family of IL-1-related cytokines has been discovered, and their crucial role in many gastrointestinal and liver diseases has been studied in detail. Today, the IL-1 family comprises 22 members, including 11 cytokines and 11 receptors. IL-1 signalling cascades share similarities with Toll-like receptors, initiating acute-phase reactions to environmental and endogenous threats, and are particularly involved in orchestrating innate immune responses, which are the basis of many gastrointestinal and liver disorders. In this article, we discuss the role of the main IL-1 family members in gastrointestinal and liver diseases, focusing on preclinical and clinical research, and we contemplate opportunities for clinical applications.</p>