Proton pump inhibitors (PPIs), long thought to be safe, are associated with a number of nonkidney adverse health outcomes and several untoward kidney outcomes, including hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, kidney failure, and increased risk for all-cause mortality and mortality due to chronic kidney disease. PPIs are abundantly prescribed, rarely deprescribed, and frequently purchased over the counter. They are frequently used without medical indication, and when medically indicated, they are often used for much longer than needed.