The innate immune sensors activate interferon-driven antiviral responses upon recognition of pathogen-associated molecular patterns (PAMPs) and serve as a rheostat for the metabolic activity of the microbiota and its exposure to diet, xenobiotics, and infections. The ability to modulate innate immune sensors opens new ways to novel anti-viral and anti-inflammatory drugs, and therapies against cancer and many aging-associated metabolic, neoplastic, autoimmune or autoinflammatory disorders. The cGAS/OAS family of innate immune sensors is among the most promising targets for the development of new antimicrobial and immunomodulatory agents. cGAS/OAS share a highly conserved structure of the active sites with other nucleotide triphosphate transferases (NTPTs). Targeting active sites of cGAS/OAS may interfere with many important biological processes through unspecific inhibition (cross-reactivity). Allosteric regulation can solve the cross-reactivity problem and help develop specific activity modulators of the innate immune sensors.