Nucleic acids are potent inducers of the antiviral type I interferons (IFN) and therefore represent prototypic PAMPs in viral infections. Innate nucleic acids sensors patrol the cytoplasm for the presence of RNA and DNA but have only a limited capacity to discriminate between endogenous and exogenous nucleic acids. Therefore mechanisms evolved that prevent the accumulation of endogenously derived nucleic acids. In Aicardi-Goutières syndrome (AGS), which represents a rare monogenic variant of the prototypic autoimmune disease systemic lupus erythematosus, genetic defects of these mechanisms result in production of large amounts of type I IFN. SAMHD1 is an intracellular nuclease that degrades RNA and DNA and cleaves deoxynucleotides (dNTP) into nucleosides and inorganic triphosphate, mutation of which cause AGS. The nucleotide triphosphohydrolase also confers antiretroviral activity to SAMHD1, as dNTP degradation was shown to represent a major block to reverse transcription of retroviruses. How and why SAMHD1-deficent cells activate the type I IFN system is not known so far. Furthermore, a comprehensive analysis of the antiretroviral potential of mouse SAMHD1 is still lacking.