The chapter first reviews evidence regarding the association between the psychiatric and medical disorders in children. It familiarizes clinicians with the range of medical or neurobiologic processes that might potentially contribute to the development of childhood psychopathology. The chapter hopefully sensitizes the clinician to the potential impact of underlying biologic processes on clinical psychiatric presentation. It provides a few guidelines for the clinician in the evaluation of children and adolescents presenting with psychopathology. Finally, the chapter summarizes a set of practical issues related to the evaluation and treatment of children with potentially co-occurring medical and psychiatric syndromes. Children with focal brain lesions face an elevated risk for psychiatric disorders, particularly behavior disorders. Based on this well-recognized association, an assessment of perinatal history and a neurologic examination have become an integral component of the comprehensive psychiatric evaluation in children and adolescents.