The host immune response is initiated by pattern recognition receptors (PRR) when triggered by specific ligands known as pathogen-associated molecular patterns (PAMP). Toll-like receptor 9 is highly expressed in plasmacytoid dendritic cells and is well described as a PRR for CpG DNA which induce the production of cytokines and type I interferons. In this issue of The EMBO Journal, Rigby et al identify RNA-DNA hybrids as a novel PAMP specifically recognized by TLR9 in dendritic cells.