Proton pump inhibitors (PPIs) are widely prescribed to treat a number of gastrointestinal disorders due to excessive acid production. While effective and safe, adverse renal effects have been described. Most concerning is the ever increasing number of cases of acute interstitial nephritis (AIN) associated with PPI therapy. It appears to be a class effect as all PPIs have been documented to cause AIN. Several adverse drug event registries now note PPIs as the most common cause of drug-induced AIN. While most patients recover kidney function, many are left with some level of chronic kidney disease. Hyponatremia is an extremely rare complication and is thought to result from inappropriate ADH secretion. Interactions with calcineurin inhibitors may occur with certain PPIs when used in susceptible patients, particularly those with polymorphisms in the cytochrome P450-2C19 enzyme gene. This paper will critically review the effect of PPIs on the kidney.