The recognition of DNA through the cGAS-STING pathway plays a critical role in antiviral immunity, but can also drive maladaptive immune responses underlying several pathological conditions. Despite its importance, understanding the organization of cGAS-STING signaling axis in the 3D space of a cell is relatively limited. In this review, we discuss recent progress in understanding the spatial coordination of DNA-induced cGAS-STING activity and its relevance in balancing innate immune responses toward (self-) DNA. We also consider the importance of context-specific co-factors and end by suggesting interesting areas for further research into spatial aspects of DNA-induced innate immunity.