The development of effective acid-suppression therapy (particularly PPIs) has revolutionized the treatment of acid-related diseases. Despite the overall effectiveness of these agents, they have some shortcomings, including a delayed onset of action, incomplete acid suppression in the majority of patients, and the need for ingestion before a meal to achieve maximal efficacy. Attempts to overcome these issues have included the development of isomeric PPIs (such as esomeprazole), alterations in drug delivery (such as delayed-release dexlansoprazole), and combined therapy with nonenterically coated PPIs and antacids (such as 'naked' omeprazole combined with sodium biocarbonate). Other acid-suppression agents in development or in late-phase trials include potassium-competitive acid blockers, new histamine receptor 2 antagonists, and gastrin antagonists. Although these agents could potentially achieve complete gastric acid suppression, risks may be associated with this level of suppression, including enteric infections and malabsorption of nutrients such as vitamin B(12), iron and calcium. This Review provides an update on the status of acid-suppression therapy and discusses directions for future research.