Proton Pump Inhibitors (PPIs) are widely used in the treatment of acid-peptic diseases. Their mechanism of action involves inhibition of the H-K-adenosine triphosphatase enzyme present in the parietal cells of the gastric mucosa. Because PPIs are the most potent inhibitors of gastric acid secretion available, they effectively alleviate acid-peptic symptoms and facilitate healing of inflamed or ulcerated mucosa. Although the use of PPIs is nowadays short term in patients with Helicobacter pylori-related peptic ulcer disease, these drugs are increasingly used long term, frequently for a lifetime, in patients with typical or atypical symptoms of gastro-oesophageal reflux disease, and in NSAID or aspirin users at risk for gastrotoxicity and related complications, such as bleeding, perforation and gastric outlet obstruction. This review outlines the essentials of PPI pharmacology, the safety and adverse profiles of the various available agents, and balances them against their clinical short- and long-term benefits. PPI use, prophylactically or with a therapeutic intent may also be combined with other strategies, such as endoscopic therapy, surgery or antibacterial use. Various clinical endpoints, such as symptom relief, mucosal healing, prevention of disease recurrence or complications, and cancer chemoprevention, are discussed and unmet needs are highlighted.