Radiotherapy is used in the treatment of approximately 50% of all malignancies including gastrointestinal cancers. Radiation can be given prior to surgery (neoadjuvant radiotherapy) to shrink the tumour or after surgery to kill any remaining cancer cells. Radiotherapy aims to maximize damage to cancer cells, while minimizing damage to healthy cells. However, only 10-30% of patients with rectal cancer or oesophageal cancer have a pathological complete response to neoadjuvant chemoradiation therapy, with the rest suffering the negative consequences of toxicities and delays to surgery with no clinical benefit. Furthermore, in pancreatic cancer, neoadjuvant chemoradiation therapy results in a pathological complete response in only 4% of patients and a partial pathological response in only 31%. Resistance to radiation therapy is polymodal and associated with a number of biological alterations both within the tumour itself and in the surrounding microenvironment including the following: altered cell cycle; repopulation by cancer stem cells; hypoxia; altered management of oxidative stress; evasion of apoptosis; altered DNA damage response and enhanced DNA repair; inflammation; and altered mitochondrial function and cellular energetics. Radiosensitizers are needed to improve treatment response to radiation, which will directly influence patient outcomes in gastrointestinal cancers. This article reviews the literature to identify strategies - including DNA-targeting agents, antimetabolic agents, antiangiogenics and novel immunotherapies - being used to enhance radiosensitivity in gastrointestinal cancers according to the hallmarks of cancer. Evidence from radiosensitizers from in vitro and in vivo models is documented and the action of radiosensitizers through clinical trial data is assessed.