Type 1 interferonopathies represent a group of genetically determined rare diseases caused by defects of the innate immune system. Central to all type 1 interferonopathies is a dysregulation of the antiviral type 1 interferon (IFN) axis, which results in constitutive overproduction of type 1 IFN. All type 1 interferonopathies present as systemic inflammatory disorders characterized by autoinflammation and autoimmunity. Although the clinical spectrum is highly variable and broad, neurological and cutaneous manifestations represent the most salient findings. Chronic type 1 IFN activation is due to defects in pathways affecting the metabolism or the immune recognition of intracellular nucleic acids. The current understanding of the molecular mechanisms underlying type 1 interferonopathies indicates that an immunomodulatory intervention targeting the type 1 IFN axis might be of therapeutic value.