Nicotinamide adenine dinucleotide (NAD) metabolism is integrally connected with the mechanisms of action of radiation therapy and is altered in many radiation-resistant tumors. This makes NAD metabolism an ideal target for therapies that increase radiation sensitivity and improve patient outcomes. This review provides an overview of NAD metabolism in the context of the cellular response to ionizing radiation, as well as current therapies that target NAD metabolism to enhance radiation therapy responses. Additionally, we summarize state-of-the-art methods for measuring, modeling, and manipulating NAD metabolism, which are being used to identify novel targets in the NAD metabolic network for therapeutic interventions in combination with radiation therapy.