RNA delivered to the endosome is detected by TLR3, in the case of long dsRNA or its mimic poly(I:C) and short dsRNA, or by TLR7, in the case of siRNA and single-stranded RNA (ssRNA). RNA delivered to the cytosol can be recognized by cytosolic helicases. The RNA helicase RIG-I detects RNA carrying a triphosphate group at the 5′ end (5′-PPP) and possibly blunt-end short RNA and intermediate dsRNA. Melanoma differentiation-associated protein-5 (MDA-5) detects long dsRNA. Long dsRNA also binds to RNA-binding PKR, but activation of IRF3 and IRF7 and subsequent type I IFN induction by PKR is controversial (as indicated by question mark). TLRs signal via TIR domain–containing adapter inducing IFN-β (TRIF) (in the case of TLR3) to activate IRF3 and NF-κB or via MyD88 (in the case of TLR7) to activate IRF7 and NF-κB. RIG-I and MDA-5 signal via IFN-β promoter stimulator-1 (IPS-1) to induce IRF7 and NF-κB. Depending on the cell type and its receptor expression pattern (e.g., ECs, myeloid DCs), recognition of RNA leads to the production of type I IFNs (e.g., IFN-α/β), and of proinflammatory cytokines or may lead to the modulation of cell-specific functions. In the study reported by Judge et al. (18) in this issue of the JCI, immunorecognition of siRNA is avoided by chemical modification and by the specific mode of delivery.