Prescription opioid use has increased in recent decades. Although opioids provide effective pain control, their use may be associated with the risk of misuse. Opioid misuse (OM) is prevalent among adolescents and young adults (AYAs). Opioids are necessary to treat cancer-related pain; however, oncology patients are not immune to medication misuse. Research examining OM among AYAs with cancer is scarce. This article examines the risk factors described in the general adult and adolescent medication abuse literature and aims to provide recommendations for practice in the AYA oncology population. The following risk factors should be examined in AYA oncology patients to determine their relevance: age, sex, behavioral and academic problems, psychological conditions, and a history of illicit drug use/abuse. To maintain the delicate balance of providing adequate pain relief while protecting patients from the risk of OM, clinicians must consider potential risk factors, motivating factors, and individual behaviors. Placing these challenges in perspective, this review provides clinical considerations, recommendations, and intervention strategies for OM prevention in AYA oncology patients.