Proton pump inhibitors (PPIs) are currently the most effective drugs inhibiting hydrochloric acid secretion. They have replaced histamine type 2 receptor antagonists in the majority of clinical indications, for example, functional dyspepsia, gastroesophageal reflux disease, or drug‑induced upper gastrointestinal tract injury. High prevalence of acid‑related upper gastrointestinal tract diseases, as well as the potency, good tolerance, and acceptable costs of treatment with PPIs have largely increased their use in hospitals and outpatient clinics. At present, PPIs are used more frequently, often long‑term and in high doses, and not necessarily according to the current recommendations. PPI‑induced inhibition of hydrochloric acid secretion causes iatrogenic hypochlorhydria and hypergastrinemia, which may result in parietal cell hypertrophy and enterochromaffin‑like cell hyperplasia, exposing patients to rebound hydrochloric acid hypersecretion. It is believed that this phenomenon may be responsible for failure to discontinue pharmacotherapy with PPIs and to their overuse. As a result, an inappropriate, especially chronic, treatment increases the risk of some side effects as well as individual and institutional expenditures. Therefore, a reasonable approach to clinical indications, dosing, and treatment regimen in each individual patient should be recommended.