Purpose of Review <p>Fifteen years after the initial description of type I interferonopathies, this review aims to provide an updated overview of the field by integrating recent genetic and mechanistic advances. It also seeks to outline practical diagnostic approaches and highlight current and emerging targeted therapeutic strategies.</p> Recent Findings <p>Type I interferonopathies are a group of monogenic autoinflammatory diseases caused by inappropriate activation of type I interferon signaling. Multiple pathogenic mechanisms have been identified, including abnormalities in nucleic acid metabolism or sensing, constitutive activation of innate immune pathways, proteasome dysfunction, endosomal Toll-like receptor hyperactivation, and impaired negative regulation of IFNAR signaling. These mechanisms result in overlapping neuroinflammatory, cutaneous, and systemic manifestations, with variable severity and often significant morbidity and mortality.</p> Summary <p>Advances in the understanding of the molecular basis of type I interferonopathies have refined their classification and improved diagnostic strategies. These insights are paving the way for more precise, mechanism-based treatments, offering promising perspectives for patient management despite the persistent severity of these disorders.</p>