How many different cytosolic sensors exist for nucleic acids? Our data suggest that sensing of c-di-GMP occurs via a novel cytosolic immunosurveillance pathway. Known nucleic acid sensors include Mda5 and RIG-I, which sense viral RNA and signal via MAVS, as well as DAI, a putative sensor of DNA that signals independently of MAVS. Based on the finding that most cell types, including MEFs, can still respond to DNA in the absence of DAI (Ishii et al., 2008) , it has been proposed that an additional DNA sensor must exist and that MEFs express both of these sensors . Our results now suggest that there is at least one additional nucleic acid sensor in the cytosol, because we find that MEFs do not B. Beutler (The Scripps Research Institute, La Jolla, CA), and RAW-B cells were obtained from G. Barton. Animal protocols were approved by the University of California, Berkeley Animal Care and Use Committee.