AbstractHaving an appreciation for neurobiologic complexity in developmentally disabled children and adolescents with behavior disorders improves our ability to treat them with drugs that have become increasingly specific in their effects. Reductionist analysis of phenotypic and genotypic disorders improves our understanding of the pathogenesis of unique patterns of adverse behaviors. Although drugs can be effective for treating specific behaviors, the cerebral mechanisms underlying these behaviors are not simple or linear in their pathways from genotype to phenotype. Our emerging knowledge about Lesch‐Nyhan disease demonstrates unexpected complexity from a single abnormal gene of purine metabolism and its diverse effects on cells, receptors, and neurotransmitters that produce characteristic self‐injurious behaviors. Several hypotheses for pathogenesis suggest ways that a defective gene might affect the developing brain and strategies for treatment. For disorders that have several abnormal genes, such as autism and bipolar disorder, biologic effects are likely to be even more complex due to gene interactions and compounded with added environmental effects, learning, and experience. There is a high incidence of comorbidity in conditions that affect behavior in children with mental retardation and developmental disabilities. Accurate diagnoses and follow‐up are essential for advanced neuropharmacology to be effective. Guidelines for the evaluation and treatment of patients who have comorbid neuropsychiatric disorders are suggested. MRDD Research Reviews 1998;4:26–35. © 1998 Wiley