Proton pump inhibitors (PPIs) are among the most widely used agents in the world. The prevalence of reflux disease is increasing, as is the incidence of oesophageal adenocarcinoma, a complication that is strongly correlated with chronic reflux disease. Although these agents are generally safe, a number of potential side effects have been described and a careful assessment of the risks and benefits of PPI therapy is required in all patients being prescribed long-term therapy. Overutilization of PPIs is a problem in clinical practice and needs further attention. PPI use has been associated with osteoporosis and bone fracture, hypomagnesaemia, the development of gastric polyps, enteric infections, interstitial nephritis and pneumonia. Patients on long-term therapy should be periodically evaluated for the indications for continued therapy. Despite widespread publicity in the lay press, and regulatory guidance regarding a number of associations, the evidence for serious side effects is poor and the risk of confounding remains a real possibility for many associations. Patients are more concerned about the absolute risk of developing a complication than a relative risk. The absolute risk of all the complications attributed to PPIs is low and patients who need long-term PPI therapy need a clear discussion of the available data on the risk of therapy and also a discussion of the risk of continued reflux.