Major depressive disorder is a common, chronic, recurring, and disabling illness in children and adolescents. Epidemiologic data suggest that the mean age at onset for depression is becoming younger. Antidepressants are widely used in pediatric patients despite a relatively small evidence base from randomized, controlled studies. Compared with the adult population, there are very few controlled studies of antidepressants in children and adolescents, and the studies that have been conducted do not unambiguously demonstrate efficacy. These findings in general are contrary to clinicians' experiences with antidepressants in this population. The different factors associated with the outcome of antidepressant studies in children and adolescents are reviewed. Developmental issues in pediatric patients, such as age of puberty and maturity of neural circuitry, are considered in the context of failed clinical trials. Review of existing controlled trials demonstrates a wide variety in study methodology. Factors such as the study location, methods of patient recruitment, small sample sizes, inclusion/exclusion criteria, study design, and choice of outcome measures all influence the ability of a study to detect differences between an antidepressant and placebo. In the current atmosphere of increased concern about antidepressant side effects, including suicidality, it is increasingly important that clinicians who treat depressed children and adolescents make informed therapeutic decisions based on data from well-controlled clinical trials.