The cGAS–STING pathway is an evolutionarily conserved immune signaling pathway critical for microbial defense. Unlike other innate immune pathways that largely rely on stationary cascades of signaling events, STING is highly mobile in the cell. STING is activated on the ER, but only signals after it arrives on the Golgi, and then it is quickly degraded by the lysosome. Each step of STING trafficking through the secretory pathway is regulated by host factors. Homeostatic STING trafficking via COPI-, COPII-, and clathrin-coated vesicles is important for maintaining baseline tissue and cellular immunity. Aberrant vesicular trafficking or lysosomal dysfunction produces an immune signal through STING, which often leads to tissue pathology in mice and humans. Many trafficking-mediated diseases of STING signaling appear to impact the central nervous system, leading to neurodegeneration. Therefore, STING trafficking introduces a new dimension of immune signaling that likely has broad implications in human disease.