The term dual-diagnosis refers to a person with mental retardation and a psychiatric disorder. Most children with Down syndrome (DS) do not have a psychiatric or neurobehavioral disorder. Current prevalence estimates of neurobehavioral and psychiatric co-morbidity in children with DS range from 18% to 38%. We have found it useful to distinguish conditions with a pre-pubertal onset from those presenting in the post-pubertal period, as these are biologically distinct periods each with a unique vulnerability to specific psychiatric disorders. Due to the increased recognition that psychiatric symptoms may co-occur with mental retardation, and are not inextricably linked to cognitive impairment, these conditions are considered treatable, in part, under a medical model. Improvement in physiologic regulation, emotional stability, and neurocognitive processing is one of the most elusive but fundamental goals of pharmacologic intervention in these disorders.