The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer. Genomic instability, a major driver of cancer and age-related diseases, poses a threat to human health and longevity. However, cellular programs maintain genome integrity and prevent malignancy. Cells may return to normal function if genetic lesions are repaired, enter senescence if damage is persistent, or undergo programmed cell death if damage is intolerable. DNA damage response (DDR) is involved in genome integrity and cell fate, but genomic instability also triggers inflammatory responses. In tissue culture, DNA-damaging agents induce type I IFNs and cytokines. Cells with nuclear DNA damage become more resistant to viral infections. In vivo studies show that chemotherapy and radiation induce type I IFN signaling in tumors to promote antitumor immunity. DNA damage also enhances NKG2D ligand expression, attracting NK cells and CD8 T cells to eliminate damaged cells. Recent studies have provided mechanistic insights into how DNA damage induces type I IFNs and other immune-regulatory cytokines. A cytosolic DNA sensing pathway is the major link between DNA damage and innate immunity. DNA in the cytoplasm acts as a danger-associated molecular pattern (DAMP) to trigger immune responses. cGAS detects DNA as a DAMP and induces type I IFNs and other cytokines. DNA binds to cGAS in a sequence-independent manner, inducing a conformational change that allows cGAS to convert GTP and ATP into cGAMP. cGAMP activates STING, which translocates to the Golgi apparatus and activates TBK1 and IRF3. STING also activates NF-κB, which functions with IRF3 to turn on type I IFN transcription. The cGAS–STING pathway plays a pivotal role in immunity against microbial pathogens. cGAS senses cytoplasmic DNA as a result of nuclear DNA damage. DNA damage in the nucleus leads to cytoplasmic DNA accumulation, notably in the form of micronuclei. Micronuclei are small, DNA-containing organelles that resemble satellites to the primary nuclei. They are products of chromosome damage due to genotoxic stress and chromosome missegregation. Micronuclei rupture, exposing DNA to cGAS. DNA damage also induces cytoplasmic DNA accumulation into "speckles." Cytoplasmic DNA speckles contain mostly single-stranded DNA. ssDNA induces less type I IFN compared to dsDNA. Stem-loop–forming ssDNA sequences in HIV reverse transcripts have high cGAS activation potential. Accumulation of ssDNA in Trex1-deficient cells is associated with chronic IFN induction and autoinflammatory phenThe cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer. Genomic instability, a major driver of cancer and age-related diseases, poses a threat to human health and longevity. However, cellular programs maintain genome integrity and prevent malignancy. Cells may return to normal function if genetic lesions are repaired, enter senescence if damage is persistent, or undergo programmed cell death if damage is intolerable. DNA damage response (DDR) is involved in genome integrity and cell fate, but genomic instability also triggers inflammatory responses. In tissue culture, DNA-damaging agents induce type I IFNs and cytokines. Cells with nuclear DNA damage become more resistant to viral infections. In vivo studies show that chemotherapy and radiation induce type I IFN signaling in tumors to promote antitumor immunity. DNA damage also enhances NKG2D ligand expression, attracting NK cells and CD8 T cells to eliminate damaged cells. Recent studies have provided mechanistic insights into how DNA damage induces type I IFNs and other immune-regulatory cytokines. A cytosolic DNA sensing pathway is the major link between DNA damage and innate immunity. DNA in the cytoplasm acts as a danger-associated molecular pattern (DAMP) to trigger immune responses. cGAS detects DNA as a DAMP and induces type I IFNs and other cytokines. DNA binds to cGAS in a sequence-independent manner, inducing a conformational change that allows cGAS to convert GTP and ATP into cGAMP. cGAMP activates STING, which translocates to the Golgi apparatus and activates TBK1 and IRF3. STING also activates NF-κB, which functions with IRF3 to turn on type I IFN transcription. The cGAS–STING pathway plays a pivotal role in immunity against microbial pathogens. cGAS senses cytoplasmic DNA as a result of nuclear DNA damage. DNA damage in the nucleus leads to cytoplasmic DNA accumulation, notably in the form of micronuclei. Micronuclei are small, DNA-containing organelles that resemble satellites to the primary nuclei. They are products of chromosome damage due to genotoxic stress and chromosome missegregation. Micronuclei rupture, exposing DNA to cGAS. DNA damage also induces cytoplasmic DNA accumulation into "speckles." Cytoplasmic DNA speckles contain mostly single-stranded DNA. ssDNA induces less type I IFN compared to dsDNA. Stem-loop–forming ssDNA sequences in HIV reverse transcripts have high cGAS activation potential. Accumulation of ssDNA in Trex1-deficient cells is associated with chronic IFN induction and autoinflammatory phen