Activation of the receptor for advanced glycation end products (RAGE) by ligands results in proinflammatory responses. As its name implies, RAGE can bind glycans modified by the Maillard reaction, the nonenzymatic process that leads to browning of food during cooking; such glycated products can also form in the body, particularly in chronic diseases such as diabetes. Other RAGE ligands have been described, including amyloid-β fibrils and the nuclear protein HMGB1. Previous work showed that nucleic acids induced inflammatory responses through binding of intracellular receptors in the cytosol or in endosomal compartments. Now Latz, Xiao and colleagues report that RAGE binds extracellular DNA molecules, promoting their uptake into cells. The authors initially observed that cells overexpressing RAGE could accumulate DNA on their surfaces. Purified RAGE could bind different forms of DNA or RNA, with apparent affinities in the micro- to nanomolar range. Two crystal structures of the RAGE extracellular domain in complex with 22-bp DNA sequences were solved, revealing a RAGE homodimer with DNA bound in a positively charged groove formed between the two monomers. In both structures, RAGE formed contacts exclusively with the phosphate backbone of the DNA molecule, thus explaining the lack of sequence specificity. Next, the authors explored the functional consequences of the RAGE-DNA interaction. In addition to binding DNA, cells expressing RAGE were able to take up higher levels of DNA than control cells. Furthermore, both receptor and DNA could be observed in early- and late-endosomal compartments, where the DNA receptor TLR9 is located. RAGE could associate with TLR9, as seen by coimmunoprecipitation; moreover, RAGE increased the level of TLR9 activation by low amounts of DNA. Finally, the authors show that mice lacking RAGE have impaired inflammatory responses in the lungs after intranasal administration of DNA and exhibit reduced influx of neutrophils and lower levels of proinflammatory cytokines and chemokines. Altogether, the work indicates that RAGE delivers extracellular DNA into the endosomal compartment to activate TLR9 and has an important role in promoting inflammatory responses to DNA in vivo. (J. Exp. Med. doi:10.1084/jem.20120201, 30 September 2013)