Type-I interferon (IFN)-mediated immune response involves both innate and adaptive immune system and has a pivotal role in antiviral defence. A complex interplay of intracellular signaling pathways and tight regulatory systems drive the IFN activation. The observation of an aberrant stimulation of this system as a common molecular basis in peculiar inherited autoimmune and autoinflammatory disorders led to the concept of "type I interferonopathies". But the precise genetic dissection of this growing spectrum of diseases adds more and more complexity to the comprehension of this concept and a lot of unsolved questions remain such as how type I IFN can drive systemic inflammation in these clinically and genetically heterogeneous diseases.