The objective of this manuscript was to review the literature relevant to the primary care practitioner concerning comorbidity and its impact on diagnosis and treatment efficacy in adults with attention-deficit/hyperactivity disorder (ADHD). A MEDLINE literature review was performed using the keywords: attention-deficit/hyperactivity disorder; psychiatric comorbidity; bipolar disorder; major depressive disorder; oppositional defiant disorder; conduct disorder; and substance use disorder. The authors assessed and summarized literature identified as relevant to primary care practitioners. Results demonstrated high rates of psychiatric comorbidity in patients with ADHD. These comorbid disorders, coupled with the differing characteristics of ADHD symptoms in adults versus children, may complicate accurate diagnosis and treatment of ADHD. Controlled clinical trials indicate that the presence of comorbidity does not substantially alter the safety and efficacy of ADHD pharmacotherapy and that treatment of ADHD can sometimes improve symptoms of the comorbid disorder. Although rates of psychiatric comorbidity are high in adults with ADHD, available data suggest that the benefits of pharmacotherapy for ADHD are not compromised by the presence of psychiatric comorbidity.