Addiction is complex and multifactorial. Recognition provides the opportunity to provide potentially life-saving treatment. Oncology patients are not excluded from substance use disorders (SUDs) and the opioid epidemic. Patients with current or past SUDs may develop cancer, and an SUD may also develop during cancer treatment. Therefore, this unique subset of patients potentially has two fatal diseases: cancer and an SUD. Most oncology advanced practitioners (APs) are unprepared to care for SUDs in patients with cancer. Pain is one of the most common symptoms in the cancer population, and cancer-related pain is often treated with opioids. Opioid exposure increases the risk of developing an opioid use disorder (OUD). In addition, a cancer diagnosis can have a significant impact on mental health and wellness, and patients may use substances to cope with psychological distress. Drug and alcohol use exists on a continuum and while not all use is problematic, it may have adverse consequences. A cancer diagnosis provides another possibility for patients to engage in services and treatment for their unsafe use and/or addiction. The case study in this article of a patient with cancer and an SUD is an example of the challenges associated with the chronic and relapsing nature of addiction. Oncology advanced practitioners have the opportunity to positively influence outcomes through the assessment of substance use and adoption of harm reduction techniques in all patients with cancer.