Initially, the concept of autoinflammation posited that there be no involvement of autoreactive B or T cells, and no evidence of infection. These criteria served well to help establish the concept, and distinguish autoinflammatory diseases from autoimmune or infectious conditions. However, the characterisation of additional monogenic autoinflammatory diseases has established that a primary trigger of the innate immune system may also be accompanied by infection or manifestations of autoimmunity, which may even contribute to pathogenesis. This issue of Seminars in Immunopathology draws out these themes and also shows how autoinflammation can help to maintain homeostasis, which is its primary evolutionary function. Elucidating the fundamental innate immune pathways underlying autoinflammatory disease leads back to these same homeostatic parameters, to inform about how infection is sensed, and providing for new targets against chronic inflammatory disease.