Despite international initiatives to promote clinical research in pediatrics, there are still many gaps of knowledge in the use of drugs to treat this specific population. When important information cannot be derived only from clinical trials, use of available observational research tools is required. In this paper, we provide an overview of the particular interest of pharmacoepidemiological research into the evaluation of drug effects in children and adolescents. We also sought to underline the unique challenges and specific needs regarding this research. Implementation of innovative methodologies and expansion of database networks to perform necessary studies could further improve performances of observational research.