Nephrotoxicity is a serious side effect associated with ifosfamide use. It can affect up to 30% of children who are treated with this chemotherapeutic drug, and treatment may necessitate lifelong supplementations, renal dialysis, renal transplant, and in severe cases may result in death. The antioxidant n-acetylcysteine is a promising strategy for mitigating this renal toxicity. It is currently used in children for acetaminophen overdose in the 21-hour IV protocol, a dose which has also been suggested to provide renal protection against ifosfamide. Of significance, both in vitro and in vivo studies suggest n-acetylcysteine does not interfere with the antitumor actions of ifosfamide. Most importantly, n-acetylcysteine has successfully protected against ifosfamide-induced nephrotoxicity in both cell and rodent models, as well as in several paediatric cases, suggesting it should be evaluated as a treatment option for children on ifosfamide who present with renal dysfunction. The purpose of this paper is to outline strategies and recommendations for treating patients at risk or suffering from nephrotoxicity during ifosfamide therapy. These recommendations may be used when deciding who to treat, how and when to treat, as well as several considerations when exact recommendations cannot be met. They have been created to increase both the quality of care and quality of life of paediatric oncology patients.