The innate immune system is an evolutionarily conserved host defense system and is the first barrier to infection. The system utilizes genetically conserved receptors to identify the presence of microbial structures. Engagement of innate immune receptors by primarily by ligands that discriminate pathogens from the host activates programmed responses that limit pathogen expansion. Despite its ubiquitous nature, surprisingly DNA is a critical structure that triggers innate immune responses. Focusing on structural modifications or aberrant location of DNA, innate immune receptors identify physiologic stress. Inflammasomes and interferons are critical innate immune pathways that are activated by DNA. DNA binding proteins that tie recognition of DNA to both programmed responses have been identified, and their importance demonstrated in infection models. In this chapter, we discuss techniques to analyze AIM2 inflammasome and cGAS interferon activation by synthetic DNA and DNA viruses. We also discuss methods to measure the activity of these immune pathways.