Radiation therapy has been used as a critical part of our approach to cure cancer for almost 100 years. While the technology of radiation delivery has dramatically improved, the ability to personalize radiation treatments based on molecular diagnostics, or tests to define baseline differences between people, has not been applied to the field of radiation oncology. In this proposal we will develop a test to personalize radiation therapy, a test that predicts how well radiation will work on each individual cancer patients, and considers the most important endpoints for them, control of their tumor, side effects from therapy, as well as the chance of cure from their cancer. We will accomplish this through testing a new class of cancer related markers in several important resources, a collection of normal tissues with known sensitivity to radiation, a collection of patients with known side effects from radiation, control of their tumor, and cure of their cancer, and finally a large randomized study of cancer patients with known side effect, tumor control and cure. We have one marker that we have already shown to predict how well radiation works on cancer patients. By the end of this study, we will have a group of markers that can be developed as a test to offer all cancer patients getting radiation as part of their treatment, to personalize their treatment and help cure them from their cancer, while minimizing the chances that they will have side effects from treatment. The ability to personalize radiation treatment, a cornerstone of our battle against cancer, to allow the best use of this powerful treatment for each individual patient will have a very broad impact on human health.