Proton pump inhibitors (PPIs) are among the most commonly prescribed medicines and are the mainstay of treatment for gastroesophageal reflux disease. Recently, there has been an increase in the use of these medicines for unclear and inappropriate indications. Although generally well tolerated and considered to be safe, several observational studies have linked PPI use with a variety of conditions such as pneumonia, Clostridium difficile infection, fractures, hypomagnesemia, and dementia. The well-established association between PPIs and acute interstitial nephritis has raised questions about whether they may also cause acute kidney injury and chronic kidney disease. Observational studies have evaluated these possible associations. This paper reviews the currently available literature about these associations and considers their possible underlying pathophysiological mechanisms. The level of evidence-linking PPI use with acute kidney injury and chronic kidney disease is weak and does not establish causality. More research is required to explore these possible associations further. The PPIs should be used in the lowest effective dose and inappropriate use should be avoided.