Proton pump inhibitors are recognized as safe and effective in acid related disorders, and are first choices in these diseases. However, with increased clinical experiences and extended treatment duration in recent years, potential adverse effects and pathophysiological change are reported. We reviewed recent advance in knowledge and mechanism of the adverse events related to proton pump inhibitor use, including hypergastrinemia, bone fracture, infection and drug interaction with Clopidogrel. We aim to provide updated information on clinical concerns and evidences in using proton pump inhibitors.