National and state guidelines exclude special populations from their recommendations for safe prescribing of opioids, particularly those with sickle cell disease, active cancer, or receiving palliative care. Despite this exemption from the guidelines, patients with these conditions do experience significant impact on their care due to overgeneralization, limits that must be overridden, and an increased concern about stigma that drives fear and self-management of pain. Elements of safe prescribing and use of opioids should apply regardless of the situation, while simultaneously ensuring adequate pain management and access to necessary medications. Rather than limiting prescribing, the focus should be on education, destigmatization, and access. Clinicians should be fueled with resources to empower patients to achieve adequate pain management and balance it with safe use. Two experienced clinicians will synthesize evidence and experience to provide practical guidance on how to approach appropriate prescribing in practice in these special populations.