Nucleic acids from microbes were known to be immunogenic for a long time, but their sensors have been only recently identified. Two types of sensors, Toll-like receptors (TLR) and the RIG-I-like receptors (RLR), principally respond to nucleic acid. Discovery of these sensors have opened basic research as to how our immune system handles microbial nucleic acids. Recent results demonstrate that functional interaction between pathogen sensors is critically involved in the extent and type of immune responses. Moreover, responsiveness of nucleic acid-sensing TLRs is profoundly influenced by molecules associated with TLRs or with nucleic acids. Our understanding of mechanisms by which TLR responses were controlled would contribute to development of drugs such as immunostimulatory nucleic acids or small chemicals antagonizing TLRs.