Psychiatric comorbidity complicates the accurate diagnosis and effective treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. This paper examines the influence of comorbidity on treatment responsiveness in ADHD adults, the neurobiological underpinnings of comorbidity, and the potential of different pharmacologic agents to address comorbid states in ADHD. A categorical schema for neurobiological classification of ADHD subtypes is integrated with literature associating specific neurotransmitters with corresponding neurobehavioral abnormalities. Dopamine, for example, is one of several neurotransmitters implicated in bipolar disorder. Serotonin and norepinephrine are implicated in major depression and anxiety disorders, while self-medication for dopamine dysfunction may relate to substance abuse. Norepinephrine and serotonin have each been linked to aggression and impulsive antisocial behaviors. The effective treatment of ADHD with comorbid psychiatric disorders requires knowledge of the neurochemical underpinnings of each disorder and expertise in the application of appropriate pharmacologic tools. Controlled studies assessing treatment outcomes for both comorbid disorders will assist in the development of improved treatment strategies for adults with complicated ADHD.