Type I interferonopathy-associated genes are involved in the sensing and metabolism of viral RNA. Genes linked to AGS and RNaseT2-deficient leukoencephalopathy are thought to encode proteins involved in the restriction of reverse transcription of both viral- and endogenous retroelement-derived DNA. The IFIH1 gene product, MDA5, is involved in the antiviral response through the recognition of dsRNA and subsequent production of type I interferon. With interferon-inducible expression, ADAR1 acts as a suppressor of type I IFN signaling through its RNA editing activity. RNaseT2 is a lysosomal hydrolase involved in RNA metabolism. SAMHD1 limits reverse transcription though degradation of deoxynucleotides necessary for complementary DNA strand formation. Among other roles in DNA synthesis and repair, RNaseH2 is thought to degrade the RNA component of DNA-RNA hybrids formed during reverse transcription. Finally, TREX1 is involved in the regulation of the interferon-stimulatory DNA response after viral infection through metabolism of virally derived nucleotides. In the absence of functioning AGS or RNaseT2 proteins, accumulation of immunostimulatory deoxyribo- and ribonucleotides may trigger upregulation of type I interferon pathway (6, 7, 12, 25, 32, 37, 39–43).