The dangerous signature came from unintegrated DNA or episome in cytoplasm could be detected by innate immunity, but how it works is unclear. Recently, more than 10 DNA sensors have been found to connect with the DNA sensing and immune defense. The cytosolic DNA induces the type Ⅰ interferon and other cytokines depended on the stimulator of interferon genes, namely STING (also known as ERIS, MITA, MPYS, and TMEM173), which functions as a key adaptor protein in the DNA sensing pathways. Surprisingly, some investigators identified a novel nucleotidyl transferase, cGAS, which produces an endogenous second-messenger cGAMP to activate STING in the cytoplasm of mammalian cells. However, how DNA activates STING to induce protective immune responses against virus, protozoa and bacteria need to be explored further. In this review, we discuss the recent research progress regarding the DNA sensing by cGAS and the mechanisms involved in activation of STING and subsequently immune responses.