We present a case of interstitial nephritis and nephrogenic diabetes insipidus (NDI) in a patient treated with pemetrexed (500 mg/m(2)) for non-small cell lung cancer. Renal impairment and diabetes insipidus appeared after the first treatment cycle while he totally received four cycles of chemotherapy. There was not any significant myelosuppression and the patient was on regular supplementation with folic acid and vitamin B(12). He was not on any other medications and he did not receive any nephrotoxic agents. Kidney biopsy showed acute tubular necrosis together with interstitial inflammatory infiltrate of mononuclear cells and interstitial fibrosis occupying 25% of the cortex. There was not any improvement of renal function after a 2-week trial of oral prednisone. In the present case report, we review the literature for pemetrexed-induced renal toxicity and the possible mechanisms involved.