The role of ADAR1 in modulating type I IFN responses to cellular dsRNA in health and disease. In healthy cells, ADAR1 prevents inappropriate recognition of self dsRNAs as foreign, by A-to-I editing of dsRNA, thus suppressing type I IFN induction, which might otherwise cause autoimmune inflammation. In contrast, as part of the innate immune response to virus-infected cells, high levels of unedited viral dsRNA are sensed by PRRs (eg, MDA5, among others), which induces a type I IFN response, a cascade of ISG transcription, and an antiviral state. In myeloma cells, baseline ADAR1 levels vary. On lenalidomide treatment, levels of cytoplasmic dsRNA rise. As with a virus-infected cell, this dsRNA has the potential to be sensed by MDA5 and induce a type I IFN response, contributing to lenalidomide-induced cell death. However, in high-ADAR1-expressing myeloma cells, A-to-I editing reduces the burden of dsRNA that can be sensed by MDA5, dampening the dsRNA-sensing response and preventing IFN induction, thus contributing to lenalidomide resistance.