The use of complementary and alternative medicine (CAM) interventions to ameliorate cancer- and treatment-related toxicities is gaining increasing attention among clinical investigators. The National Cancer Institute supports a number of clinical studies, both descriptive and interventional, of CAM interventions across the cancer trajectory, from prevention through diagnosis and treatment, survivorship, and end of life. This report highlights the unique challenges that clinical investigators face when designing and implementing CAM clinical trials through the cooperative groups. This report focuses on 2 CAM trials that opened and accrued participants in the Children’s Oncology Group. One trial is aimed at preventing or reducing mucositis and the other at preventing chemotherapy-induced nausea and vomiting.