Gene expression signatures (GES) are a powerful tool in oncology used for classification, prognostication, and therapeutic response prediction of malignancies. In this article, we review the disease site guidelines by the National Comprehensive Cancer Network that use GES for treatment planning and clinical use. We identified 4 cancer types for which treatment decisions are frequently influenced by GES. Future developments in the field of GES are likely to include expanded data sources to personalize radiation therapy dosing and predict response to immunotherapy. Ongoing challenges in GES may be addressed to ensure that all patients with cancer benefit from precision oncology.