Encephalopathy is a potentially fatal toxicity of ifosfamide. Clinical manifestations of encephalopathy range from fatigue and confusion to coma and death. Early identification of this toxicity and prompt cessation of ifosfamide are the essential elements in the management of ifosfamide encephalopathy. Accurate prediction of this toxicity is often difficult. Based on the limited available evidence, methylene blue, an electron acceptor, may have a role in the treatment and the prevention of neurotoxicity. This paper reviews the current understanding of ifosfamide encephalopathy.