The cGAS-STING pathway has recently emerged as a critical driver of inflammation in a variety of settings, such as double-stranded DNA (dsDNA) virus infection, cellular stress, and tissue damage. The pathway senses microbial and host-derived dsDNA in the cytosol, and triggers the production of the type I interferons through the activation of TBK1 (kinase) and IRF3 (transcription factor). The detailed mechanistic understanding of the pathway has enabled the development of pharmacological agents for the treatment of chronic inflammation and cancer. STING is a transmembrane protein that localizes at the endoplasmic reticulum (ER). Once bound to cGAMP, a second messenger that is generated by dsDNA-bound cGAS, STING translocates from the ER to the Golgi. STING then activates TBK1 and IRF3 at the trans-Golgi network (TGN). Dysregulated Golgi-to-ER traffic underlies the pathogenesis of COPA syndrome, a monogenic autoinflammatory disease caused by missense mutations of coatomer protein complex subunit α (COP-α). In this chapter, I focus on emerging issues regarding the regulation of STING activation by membrane traffic between the ER and the Golgi, and also on the molecular mechanism underlying the specific activation of TBK1/IRF3 at the TGN.