The role of the cytokines and receptors of the IL-1 family in inflammation is well known. Several cytokines of the family have a powerful inflammatory activity, with IL-1β being the best-characterized factor. The inflammatory activity of IL-1 cytokines is regulated by other factors of the family, including receptor antagonists, soluble receptors and anti-inflammatory cytokines. The causative role of IL-1β is well-established in autoinflammatory diseases, mainly due to gain-of-function mutations in genes encoding the IL-1β-maturing inflammasome. Exaggerated production of IL-1β and IL-18 correlates with disease and disease severity also in several autoimmune and chronic inflammatory and degenerative pathologies, although it is not clear whether they have a causative role or are only involved in the downstream disease symptoms. A better understanding of the pathological role of IL-1 family cytokines in autoimmunity involves a deeper evaluation, in the pathological situations, of the possible anomalies in the feed-back anti-inflammatory mechanisms that in physiological reactions control and dump IL-1-mediated inflammation. Thus, we expect that IL-1 cytokines may be pathogenic only when, in addition to enhanced production, there is a concomitant failure of their control mechanisms. In this review we will examine the current knowledge on the role of IL-1 family cytokines in autoimmune and chronic inflammatory and degenerative diseases, with a particular focus on their endogenous control mechanisms, mainly based on soluble receptors/inhibitors and receptor antagonists. This will allow us to formulate a knowledge-based hypothesis on the involvement of IL-1 cytokines in the pathogenesis vs. the clinical features of these diseases.Copyright © 2020. Published by Elsevier B.V.