The lungs are constantly exposed to airborne pathogens and depend on robust innate immune surveillance for protection. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a core component of the innate immune system, plays a pivotal role in defending against respiratory infections caused by viruses, bacteria, and mycobacteria, including . Dysregulation of this pathway has been linked to several chronic lung diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and asthma. Upon sensing cytoplasmic DNA, cGAS activates the STING pathway, producing type I interferons and pro-inflammatory cytokines that drive host immune response. However, many pathogens have developed strategies to evade detection or surpass cGAS-STING signaling. This systematic review highlights the molecular mechanisms governing cGAS-STING activation, its interaction with lung pathogens, and its potential as a therapeutic agent in respiratory diseases.