DNA, as the material basis of all living cells, triggers innate immune responses through TLR9 and other cytosolic recognition receptors. In recent years, the research progress of TLR9 is mainly manifested by the following four aspects: (1) the determinants of TLR9 interacting with its ligands; (2) the mechanisms and the importance of TLR9 translocation from the endoplasmic reticulum to the endosome; (3) the roles of the endosomal acidification and maturation, and subsequent TLR9 cleavage in TLR9 signal transduction pathway; and (4) the possible mechanisms by which the organism distinguish self DNA from microbial DNA. Meanwhile, a series of experiments on TLR9 antagonists and TLR9 deficient mice confirmed the presence of TLR9independent cytosolic DNA sensors. So far, three TLR9independent DNA sensors have been found, and they are DAI, AIM2, and RNA polymerase Ⅲ.