There is an urgency to improve the evaluation of pediatric drug safety in the pre-market and post-market phases of drug evaluation. The need to improve pharmacovigilance methods concerns not only new drugs but also existing drugs that have been used for many years in an off-label manner in children. Effective methods for early detection of adverse drug reactions (ADRs) and drug safety epidemiologic studies are a pressing need in pediatrics. Moreover, the nature and severity of an ADR as well as the extent to which the suspected drug is being used, will determine how quickly the information about risk needs to be made available to users and what would be the most appropriate method of communication. Based on our experience through the Genotype-specific Approaches to Therapy in Children study, an active ADR surveillance network of pediatric hospitals across Canada, we present five strategic elements that should be included in pharmacovigilance initiatives in pediatrics: active ADR surveillance; drug or ADR targeted pharmacovigilance; trained surveillance clinicians; case-control methodology and standardized procedures for recognition; reporting and evaluating drug-induced harm. In addition, linking pharmacovigilance with pharmacogenomics to find drug safety solutions is presented as a promising strategy for knowledge generation. Finally, we discuss the importance of an efficient translation of the pharmacovigilance knowledge into clinical practice to achieve safer drug therapy in children.