The invasion of mammalian cytoplasm by microbial DNA from infectious pathogens or by self DNA from the nucleus or mitochondria represents a danger signal that alerts the host immune system¹. Cyclic GMP-AMP synthase (cGAS) is a sensor of cytoplasmic DNA that activates the type-I interferon pathway². On binding to DNA, cGAS is activated to catalyse the synthesis of cyclic GMP-AMP (cGAMP) from GTP and ATP³. cGAMP functions as a second messenger that binds to and activates stimulator of interferon genes (STING)^3-9.STINGthen recruits and activates tank-binding kinase 1 (TBK1), which phosphorylatesSTINGand the transcription factor IRF3 to induce type-I interferons and other cytokines^10,11. However, how cGAMP-boundSTINGactivates TBK1 and IRF3 is not understood. Here we present the cryo-electron microscopy structure of human TBK1 in complex with cGAMP-bound, full-length chickenSTING. The structure reveals that the C-terminal tail ofSTINGadopts a β-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold and dimerization domain of the second subunit in the TBK1 dimer. In this binding mode, the phosphorylation site Ser366 in theSTINGtail cannot reach the kinase-domain active site of bound TBK1, which suggests thatSTINGphosphorylation by TBK1 requires the oligomerization of both proteins. Mutational analyses validate the interaction mode between TBK1 andSTINGand support a model in which high-order oligomerization ofSTINGand TBK1, induced by cGAMP, leads toSTINGphosphorylation by TBK1.