OBJECTIVES: To assess the effectiveness of interventions targeting traumatic stress among children exposed to nonrelational traumatic events (eg, accidents, natural disasters, war). METHODS: We assessed research on psychological and pharmacological therapy as part of an Agency for Healthcare Research and Quality– commissioned comparative effectiveness review. We conducted focused searches of Medline, Cochrane Library, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts, and Web of Science. Two trained reviewers independently selected, extracted data from, and rated the risk of bias of relevant trials and systematic reviews. We used qualitative rather than quantitative analysis methods because of statistical heterogeneity, insufficient numbers of similar studies, and variation in outcome reporting. RESULTS: We found a total of 21 trials and 1 cohort study of medium or low risk of bias from our review of 6647 unduplicated abstracts. We generally did not find studies that attempted to replicate findings of effective interventions. In the short term, no pharmacotherapy intervention demonstrated efficacy, and only a few psychological treatments (each with elements of cognitive behavioral therapy) showed benefit. The body of evidence provides little insight into how interventions to treat children exposed to trauma might influence healthy long-term development. CONCLUSIONS: Our findings serve as a call to action: Psychotherapeutic intervention may be beneficial relative to no treatment in children exposed to traumatic events. Definitive guidance, however, requires far more research on the comparative effectiveness of interventions targeting children exposed to nonrelational traumatic events. Pediatrics 2013;131:526–539