Palliative chemotherapy can be conceptually confusing to patients and their families. When presented as an option at end of life, the decision-making process can be particularly stressful as patients and their families struggle to understand the goals of palliative chemotherapy, and examine their own values, wishes, and expectations for care. Lacking a clear definition in the literature, palliative chemotherapy is highly individualized to patients. However, applying holistic strategies during the decision-making process can mitigate stress, protect patients and families from misinformation, and ensure that they do not miss the opportunity to evaluate their options. In this narrative review for clinical application, the authors highlight key issues in palliative chemotherapy and palliative chemotherapy decision-making, and present evidence-based strategies for supporting patients and families through the decision-making process from a holistic perspective.