The concept that genetic/genomic alterations may function as surrogate biomarkers of disease response or normal tissue toxicity underpins the field of radiogenomics. Numerous hypoxia signatures have been derived that are prognostic in patients undergoing radiotherapy. Numerous hypoxia signatures are not specific for radiation given that they are also prognostic in surgically treated patients. However, they help to provide the expertise in developing transcriptomic signatures for radiation oncology and progressing these biomarkers to clinical implementation. In order to enable the creation of large cohorts of patients who received radiotherapy, the Radiogenomics Consortium (RGC) was created in 2009, which is a cancer epidemiology consortium through the Epidemiology and Genomics Research Program of the National Cancer Institute of the National Institutes of Health. Several large-scale candidate gene studies have been performed investigating either one or a small number of single nucleotide polymorphisms. These RGC big data projects enabled the identification of genetic variants associated with radiotherapy toxicity where effect sizes are small.