Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs due to the increasing incidence of acid‑related disorders, but a large number of prescriptions are issued with inappropriate indications. Despite PPIs being effective and well tolerated, there have been growing concerns about potential adverse effects associated with long‑term use of these drugs. Indeed, pharmacovigilance agencies have issued broad-based product warnings on the association between treatment with PPIs and long‑term complications, including increased risk of fractures and impaired magnesium absorption. On the contrary, despite plausible underlying biological mechanisms, the available clinical evidence for most side effects is weak or contradictory, and the benefits of PPI treatment seem to outweigh the potential adverse effects. This review aims to discuss the most important and established side effects of long-term use of PPIs and provide practical considerations for their clinical management.