Monogenic autoinflammatory diseases are defined as a group of conditions with a clinical and biological inflammatory syndrome but little or no evidence of autoimmunity. Over 17 years have passed since the discovery of the first autoinflammatory gene, MEFV, responsible for familial Mediterranean fever. Substantive progress has been made since then, highlighting the key role of the inflammasome in the maintenance of the cell homeostasis but also unravelling new pathophysiological pathways involved in these diseases. The history of autoinflammatory gene discovery demonstrates the powerfulness of next-generation sequencing approaches in linking inflammatory disorders with various overlapping phenotypes. It can be easily anticipated that new genes will be exponentially identified in the coming years. Integrating these new concepts should help to promote personalized patient care through novel therapeutic opportunities.