Methadone is a synthetic opioid with unique pharmacodynamic and pharmacokinetic properties. It is effective in treating both nociceptive and neuropathic pain, which commonly co-exist in children with cancer. Upon reviewing the literature describing the use of methadone in pediatric oncology patients, publications are limited in number and low in quality of evidence; nevertheless, there is support for the safety and efficacy of methadone in treating pain in children with cancer, particularly when pain is refractory to conventional treatment. Although the risk of life-threatening arrhythmia is commonly cited as an argument against the use of methadone, our review of the literature did not support this finding in children. Further evaluation with prospective studies is warranted to develop evidence-based recommendations for the use of methadone in pediatric oncology.