The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a critical innate immune pathway that, following engagement by DNA, promotes distinct immune effector responses that can impact virtually all aspects of tumorigenesis, from malignant cell transformation to metastasis. Here we address how natural tumor-associated processes and traditional cancer therapies are shaped by cGAS-STING signaling, and how this contributes to beneficial or detrimental outcomes of cancer. We consider current efforts to target the cGAS-STING axis in tumors and highlight new frontiers in cGAS-STING biology to inspire thinking about their connection to cancer.