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At least 20% of children in the U.S. are highly vulnerable because they lack healthcare and protection. Several factors produce vulnerability: trauma, disruptions of parenting, poverty, involvement in the juvenile justice and/or child welfare systems, residence in restrictive settings, and problems related to developmental disabilities. These children receive psychotropic medications at high rates, raising numerous concerns.The authors begin this review with a description of the population of highly vulnerable children. They then follow this with a review of the effectiveness and side effects of psychotropic medications for their most common diagnoses, using the highest-quality systematic reviews identified by multiple database searches.Highly vulnerable children receive numerous psychotropic medications with high rates of polypharmacy, off-label use, and long-term use, typically in the absence of adjunctive psychosocial interventions. The current evidence contravenes these trends. Future studies of psychotropic medications in vulnerable children should include long-term effectiveness trials and polypharmacy in conjunction with evidence-based, family-centered, psychosocial treatments.