Immunological defense depends on the ability of the innate immune system to recognize invading microbes as foreign and thus eliminate them. The Toll-like receptors (TLRs) help detect foreign invaders by sensing various pathogen-associated molecules, including microbial RNA and DNA. At present, it is unclear whether and how the immune system distinguishes between microbial and self nucleic acids, as host-derived RNA and DNA also stimulate TLRs. In addition, recent studies have revealed the existence of TLR-independent pathways that are activated in response to microbial and host nucleic acids.