The cGAS–STING pathway has emerged as a critical mediator of inflammation in various contexts, including infection, cellular stress, and tissue damage. This pathway senses and regulates the cellular response to microbial and host-derived DNAs, which serve as danger-associated molecules. Recent advances in understanding the structural and molecular biology of the cGAS–STING pathway have led to the development of selective small-molecule inhibitors, which have potential therapeutic applications in inflammatory diseases. The pathway is activated by the binding of cGAS to double-stranded DNA (dsDNA), leading to the production of cyclic GMP-AMP (cGAMP), a potent agonist of STING. STING then oligomerizes and recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3), initiating the synthesis of type I interferons and other inflammatory cytokines. The cGAS–STING pathway is also involved in autophagy, cell death, and intercellular communication through cGAMP. Dysregulation of this pathway can lead to autoinflammatory, autoimmune, and degenerative diseases. Recent studies have identified specific mutations in genes involved in the cGAS–STING pathway, such as *STING1*, *TREX1*, *RNASEH2A*, *RNASEH2C*, *SAMHD1*, and *DNASE2*, that contribute to monogenic autoinflammatory disorders. Additionally, the pathway plays a role in systemic autoimmune diseases like systemic lupus erythematosus (SLE). Targeting the cGAS–STING axis with selective inhibitors offers a promising therapeutic strategy for treating inflammatory and autoimmune diseases.The cGAS–STING pathway has emerged as a critical mediator of inflammation in various contexts, including infection, cellular stress, and tissue damage. This pathway senses and regulates the cellular response to microbial and host-derived DNAs, which serve as danger-associated molecules. Recent advances in understanding the structural and molecular biology of the cGAS–STING pathway have led to the development of selective small-molecule inhibitors, which have potential therapeutic applications in inflammatory diseases. The pathway is activated by the binding of cGAS to double-stranded DNA (dsDNA), leading to the production of cyclic GMP-AMP (cGAMP), a potent agonist of STING. STING then oligomerizes and recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3), initiating the synthesis of type I interferons and other inflammatory cytokines. The cGAS–STING pathway is also involved in autophagy, cell death, and intercellular communication through cGAMP. Dysregulation of this pathway can lead to autoinflammatory, autoimmune, and degenerative diseases. Recent studies have identified specific mutations in genes involved in the cGAS–STING pathway, such as *STING1*, *TREX1*, *RNASEH2A*, *RNASEH2C*, *SAMHD1*, and *DNASE2*, that contribute to monogenic autoinflammatory disorders. Additionally, the pathway plays a role in systemic autoimmune diseases like systemic lupus erythematosus (SLE). Targeting the cGAS–STING axis with selective inhibitors offers a promising therapeutic strategy for treating inflammatory and autoimmune diseases.