Background: PPIs are frequently used in hospitals, primary health care centers and private clinics. The adverse effects and interactions are numerous so, physicians’ knowledge including accurate indications after confirmations of diagnosis, duration of use and follow-up are an essential part of the treatment process. Aim: The purpose of this review tis o help health care professionals to prescribe the PPIs wisely and appropriately. Objective: To undertake a review of the literature relating to the long-term use of PPIs Data Sources: United States, Food and Drug Administration [FDA], PubMed, Scopus, Science Direct, Wiley, Google Scholar, major clinical guidelines, and governmental agencies. Data Extraction: The 2 reviewers Musa Basheer Mansour and Sara Ahmedana [MBM and SEA] independently assessed the qualities of the extracted studies and summarized data of the studies for outcomes of interest and performed quality assessments based on review of published articles and the data sources. Results: We reviewed the available evidence and summarized the long-term use of PPIs as indicated by major clinical guidelines, governmental agencies, and published studies. For instance, United States, Food and Drug Administration, American Gastroenterological Association, American Academy of Family Physicians, British National Formulary, National Institutes of Health, Randomized controlled trials, Systematic review, Meta-analysis and Observational studies. Conclusion: This review will provide clinical practice with research evidence-based guidelines. Clinicians and physicians should follow the major clinical guidelines and governmental agencies to prescribe PPIs, follow their patients regularly to achieve the goals of treatment, to avoid adverse effects, drug interactions and reduce the costs. Keywords: Proton Pump Inhibitors, Food and Drug Administration, Gastrointestinal Acid Disorders, Gastro-Esophageal Reflux Disorder, and peptic ulcer disease