Clinical research has led to great advances in cancer therapy for children, and a greater proportion of children than adults with cancer participate in clinical trials. Despite this success, there remain important ethical challenges in conducting this research. There are challenges in obtaining informed consent and assent when children are research subjects; challenges arising from study design issues in phase III, II, or I clinical trials; and challenges related to the development of new classes of drugs, especially molecularly targeted therapies. It is important for researchers and clinicians to understand these challenges so that progress in cancer treatment is achieved in a sound ethical and regulatory fashion.