Adverse drug reactions (ADRs) are common and important complications of drug therapy for children. The risk for ADRs changes over childhood, as do the nature and types of ADRs. Importantly, the risk and nature of ADRs in children are markedly different from those of adults, and adult data cannot be relied on to guide safe drug therapy in children. There are groups of children, notably those with complex and chronic diseases, who are at substantial risk for ADRs. The evaluation of an undesired effect during therapy is ideally accomplished by an organized approach that is a skill that clinicians who care for children-especially those children at high risk for ADRs must have. Additionally, clinicians as well as drug regulatory agencies and industry need to be both vigilant and astute as well as aware that ADRs in children are often different in nature and frequency from those in adults. The increasing use of pharmacogenomics to guide drug dosing and the increasing number of biological agents will provide new sets of challenges to clinicians over the next decade.