More than 15 years after the launch of omeprazole in 1988, proton-pump inhibitors remain central to the management of acid-suppression disorders and are unchallenged with regard to their efficacy and popularity among doctors and patients. They are considered safe despite early concerns about the possibility of an association with cancer and gastric atrophy; current concerns about long-term proton-pump inhibitor therapy are centred mainly on a possible association with fundic gland polyps and between Helicobacter pylori and gastric atrophic changes. Long-term proton-pump inhibitor usage accounts for the majority of the total proton-pump inhibitor usage. Long-term usage is difficult to define and most patients take proton-pump inhibitors non-continuously. Data indicate that a substantial proportion of long-term users do not have a clear indication for their therapy and there is thus room for reduction or rationalization of treatment. Overall, on-demand therapy is more cost-effective than continuous therapy and should be considered wherever possible.