Cell-free, immuno-stimulatory DNA is recognized in the cytoplasm of cells as a universal danger signal by the innate immune system. We are using genome-scale RNAi and CRISPR/Cas9 approaches in primary human cells to identify important new players in the cGAS-STING pathway of innate cytoplasmic DNA sensing, which has been implicated as the primary sensor for many fungal, bacterial, viral pathogens, and even for neoplastic cells. We aniticpate that key regulators of this pathway will represent important targets for boosting innate immune responses to microbial pathogens and cancer.