The innate immune system is responsible for detecting microbial invasion of the cell and for stimulating host defense countermeasures. These anti‐pathogen procedures include the transcriptional activation of powerful antiviral genes such as the type I interferons (IFNs) or the triggering of inflammatory responses through interleukin‐1 (IL‐1) production. Over the past decade, key cellular sensors responsible for triggering innate immune signaling pathways and host defense have started to be resolved and include the Toll‐like receptor (TLR), RIG‐I‐like helicase, and the cytoplasmic nucleotide‐binding oligermerization domain‐like receptor families. These sensors recognize non‐self pathogen‐associated molecular patterns such as microbial lipopolysaccharides and nucleic acids. For example, TLR9 has evolved to detect CpG DNA commonly found in bacteria and viruses and to initiate the production of IFN and other cytokines. In contrast, AIM2 (absent in melanoma 2) has been shown to be essential for mediating inflammatory responses involving IL‐1β following the sensing of microbial DNA. Recently, a molecule referred to as STING (stimulator of IFN genes) was demonstrated as being vital for recognizing cytoplasmic DNA and for activating the production of innate immune genes in response to a variety of DNA pathogens and even certain RNA viruses. Comprehending the mechanisms of intracellular DNA‐mediated innate immune signaling may lead to the design of new adjuvant concepts that will facilitate vaccine development and may provide important information into the origins of autoimmune disease.