TANK-binding kinase 1 (TBK1) is a Ser/Thr kinase with a central role in coordinating the cellular response to invading pathogens and regulating key inflammatory signaling cascades. While intact TBK1 signaling is required for successful anti-viral signaling, dysregulated TBK1 signaling has been linked to a variety of pathophysiologic conditions, including cancer. Several lines of evidence support a role for TBK1 in cancer pathogenesis, but the specific roles and regulation of TBK1 remain incompletely understood. A key challenge is the diversity of cellular processes that are regulated by TBK1, including inflammation, cell cycle, autophagy, energy homeostasis, and cell death. Nevertheless, evidence from pre-clinical cancer models suggests that targeting TBK1 may be an effective strategy for anti-cancer therapy in specific settings. This review provides an overview of the roles and regulation of TBK1 with a focus on cancer pathogenesis and drug targeting of TBK1 as an anti-cancer strategy. Relevant literature was derived from a PubMed search encompassing studies from 1999 to 2020. TBK1 is emerging as a potential target for anti-cancer therapy. Inhibition of TBK1 alone may be insufficient to restrain the growth of most cancers; hence, combination strategies will likely be necessary. Improved understanding of tumor-intrinsic and tumor-extrinsic TBK1 signaling will inform novel therapeutic strategies.