Proton pump inhibitors (PPIs) are one of the most commonly prescribed classes of medications in the United States. By inhibiting gastric H/K adenosine triphosphatase via covalent binding to the cysteine residues of the proton pump, they provide the most potent acid suppression available. Long-term PPI use accounts for the majority of total PPI use. Absolute indications include peptic ulcer disease, chronic nonsteroidal anti-inflammatory drugs use, treatment of Helicobacter pylori, and erosive esophagitis. Although PPIs are generally considered safe, numerous adverse effects, particularly associated with long-term use have been reported. Many patients receiving chronic PPI therapy do not have clear indications for their use, prompting consideration for reduction or discontinuation of their use. This article reviews the indications for PPI use, the adverse effects/risks involved with their use, and conditions in which their use is controversial.