Chemotherapy and radiotherapy, both alone and in combination, remain important tools in the successful treatment of cancer. Because the oral and gastrointestinal (GI) mucosa is often significantly damaged by cancer therapy, management of these problems is an important challenge for oncologists. Such treatment complications are generally not severe or life threatening, but they can result in both treatment delays and dose reductions in potentially curative regimens. Numerous therapeutic approaches have been evaluated as prophylaxis or treatment for mucosal damage in patients undergoing cancer therapy. The results of large-scale, placebo-controlled, comparative trials demonstrate that administration of a proton pump inhibitor (PPI) can provide both significant symptom relief and prophylaxis against upper GI ulceration in patients receiving cancer chemotherapy. Although no corresponding clinical trial has been conducted in patients undergoing irradiation, PPIs are also likely to be effective in preventing gastro-oesophageal mucosal injury in such individuals. Thus, PPIs may play a crucial role in supportive care for patients undergoing cancer therapy.