Autoinflammatory diseases encompass a growing number of multisystem clinical entities with genetic or acquired defects in the innate immune system. Distinct conditions can be identified in this expanding sphere: familiar Mediterranean fever, mevalonate kinase deficiency, tumor necrosis factor receptor-associated periodic syndrome, cryopyrinopathies, idiopathic febrile syndromes, hereditary pyogenic disorders, pediatric granulomatous arthritides, complement dysregulation syndromes and Behçet’s disease. All these multifaceted conditions display episodes of seemingly unprovoked inflammation of variable duration and different severity. The main limitation to their better knowledge is the extreme fragmentation of the diagnosed cases that are spread over different centres and countries. The discovery of new molecules involved in recognizing exogenous and endogenous danger signals that lead to inflammatory responses has allowed to understand the pathways of innate immunity and to disclose new therapeutic perspectives for children with autoinflammatory diseases.