Research to elucidate the biological bases of psychopathology in children and adolescents is needed to understand pathogenesis and to develop effective and safe treatment and preventive interventions. Because of the effect of development, data collected in adults are not always applicable to youth, and direct participation of children in research is necessary. Many medications are currently used in the community to treat children and adolescents with neuropsychiatric disorders without adequate data about their safety and efficacy. Conducting research in children requires attention to specific ethical and regulatory factors. In deciding whether minors can participate in a study with potential direct benefit to the research subjects, the most important variable to consider is the balance between risks and potential benefit, in the context of the severity of the child’s condition and the available alternatives. Research with no potential benefit to the participants is guided by the concepts of minimal risk (which may apply more to normal children) and minor increase over minimal risk (perhaps more relevant to children affected by psychopathology). Recently conducted studies relevant to this issue are reviewed. Of paramount importance is the ratio of risk/scientific value of the proposed experiment. In fact, no research is justifiable, no matter how low the risk may be, unless the potential yield of the study is important and may help advance our understanding of normal functioning and mental illness.