The cGAS-cGAMP-STING pathway is essential for immune defense against pathogens. Upon binding DNA, cGAS synthesizes cGAMP, which activates STING, leading to potent innate immune effector responses. However, lacking specific features to distinguish between self and nonself DNA, cGAS-STING immunity requires precise regulation to prevent aberrant activation. Several safeguard mechanisms acting on different levels have evolved to maintain tolerance to self DNA and ensure immune homeostasis under normal conditions. Disruption of these safeguards can lead to erroneous activation by self DNA, resulting in inflammatory conditions but also favorable antitumor immunity. Insights into structural and cellular checkpoints that control and terminate cGAS-STING signaling are essential for comprehending and manipulating DNA-triggered innate immunity in health and disease.