Methadone use as a second-line agent for severe cancer-related pain is increasing in the field of hospice and palliative care. It has a number of qualities that make its use favorable, including lack of known active metabolites and presumed relative safety from adverse effects such as opioid-induced neurotoxicity (OIN). This article describes a case of a patient undergoing treatment of severe cancer-related pain who developed OIN in the setting of oral methadone use. As the use of methadone increases, more research into its pharmacologic and pharmacokinetic properties will be necessary.