Host cells have evolved a variety of sensors to detect infectious agents. These include the RIG-I-like receptors (RLRs) which recognize viral RNAs and the Toll-like receptors (TLRs) which have evolved to detect microbe specific molecules such as CpG DNA and lipopolysaccharides. These interactions trigger signaling events which activate key transcription factors such as interferon regulatory factor 3 (IRF3) and NF-κB, leading to the production of type I interferon (IFNs) and proinflammatory cytokines, which facilitate adaptive immunity. In addition there exists a key innate immune signaling pathway that has evolved to detect aberrant cytosolic DNA species, such as the genomes of bacteria or viruses following infection. This pathway is controlled by a cellular sensor referred to as STING (stimulator of interferon genes) that is activated by cyclic dinucleotides (CDN’s; cyclic di-GMP/AMP or cyclic GMP-AMP (cGAMP)) generated directly by invading bacteria, or via a DNA synthase cGAS (cGAMP synthase, also known as MB21D1) after association with viral or bacterial dsDNA. The STING pathway has been shown to be essential for stimulating host defense against an assortment of infectious agents. In addition, the extrinsic activation of STING in phagocytes via the DNA of engulfed dying cancer cells is essential for the generation of cytokines required for the efficient production of anti-tumor T cell responses. In contrast, chronic STING signaling has been shown to be associated with lethal autoinflammatory disease such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE). The activity of STING therefore requires tight control to prevent the sustained production of cytokines which are responsible for harmful autoimmune disease. Here, we will discuss the importance of STING-dependent innate immune signaling in controlling infectious disease, inflammation and cancer as well as review the importance of generating therapeutics that may control this pathway, for the prevention of a wide variety of disease.