The cGAS–STING pathway is a key mediator of inflammation in infection, cellular stress, and tissue damage. It senses and regulates responses to microbial and host-derived DNA, which are danger-associated molecules. Structural and molecular insights have enabled the development of small-molecule inhibitors targeting the cGAS–STING axis in inflammatory diseases. The pathway is activated by DNA, which is a fundamental element of life, and lacks pathogen-specific attributes, allowing it to recognize both foreign and self-DNA. This pathway is crucial for innate immune defense, but its dysregulation can lead to aberrant immune responses and disease. The pathway's activation is regulated by DNA binding, leading to cGAMP production, which activates STING. STING undergoes conformational changes, leading to oligomerization and downstream signaling, including IRF3 activation and NF-κB signaling. These processes are critical for antiviral responses and immune activation. The pathway also plays a role in autophagy, which is essential for antiviral defense and cellular homeostasis. Dysregulation of the cGAS–STING pathway can contribute to various diseases, including autoinflammatory and autoimmune conditions. Recent studies have shown that the pathway is involved in inflammatory diseases, and its activation can be modulated by various factors. The pathway's role in disease is complex, with both protective and pathological effects depending on the context. The cGAS–STING pathway is also involved in intercellular communication through cGAMP transfer, which can amplify immune responses. The pathway's activation can be influenced by various factors, including mitochondrial DNA release, genomic DNA damage, and retrotransposable elements. Mutations in genes involved in the cGAS–STING pathway can lead to monogenic diseases, such as Aicardi–Goutières syndrome and COPA syndrome. These diseases highlight the importance of the cGAS–STING pathway in immune regulation and the potential for therapeutic interventions targeting this pathway.The cGAS–STING pathway is a key mediator of inflammation in infection, cellular stress, and tissue damage. It senses and regulates responses to microbial and host-derived DNA, which are danger-associated molecules. Structural and molecular insights have enabled the development of small-molecule inhibitors targeting the cGAS–STING axis in inflammatory diseases. The pathway is activated by DNA, which is a fundamental element of life, and lacks pathogen-specific attributes, allowing it to recognize both foreign and self-DNA. This pathway is crucial for innate immune defense, but its dysregulation can lead to aberrant immune responses and disease. The pathway's activation is regulated by DNA binding, leading to cGAMP production, which activates STING. STING undergoes conformational changes, leading to oligomerization and downstream signaling, including IRF3 activation and NF-κB signaling. These processes are critical for antiviral responses and immune activation. The pathway also plays a role in autophagy, which is essential for antiviral defense and cellular homeostasis. Dysregulation of the cGAS–STING pathway can contribute to various diseases, including autoinflammatory and autoimmune conditions. Recent studies have shown that the pathway is involved in inflammatory diseases, and its activation can be modulated by various factors. The pathway's role in disease is complex, with both protective and pathological effects depending on the context. The cGAS–STING pathway is also involved in intercellular communication through cGAMP transfer, which can amplify immune responses. The pathway's activation can be influenced by various factors, including mitochondrial DNA release, genomic DNA damage, and retrotransposable elements. Mutations in genes involved in the cGAS–STING pathway can lead to monogenic diseases, such as Aicardi–Goutières syndrome and COPA syndrome. These diseases highlight the importance of the cGAS–STING pathway in immune regulation and the potential for therapeutic interventions targeting this pathway.