Proton pump inhibitors have proven to be important in the treatment of acid/peptic diseases. However, their therapeutic uses have extended over time, which may alter their risk:benefit ratio. Significant rebound acid hypersecretion has been demonstrated, which persists for at least two months. Its clinical significance remains unknown. Enhanced oxyntic gastritis may be responsible for the increased acid suppressive effects of proton pump inhibitors in H. pylori-infected patients. It remains unclear whether either H. pylori eradication or diminishing rates of infection in the developed world will therefore decrease the efficacy of proton pump inhibitors. Problems with carcinoids in rodents have not been found in man. However, the consequences of very long-term use of proton pump inhibitors remain unknown. Similarly, the development of atrophic gastritis in H. pylori-positive patients treated with proton pump inhibitors, with the long-term concern of gastric carcinoma development, remains controversial.