Psychostimulants are first-line therapy for patients with attention-deficit/hyperactivity disorder (ADHD). However, some patients are not optimal responders to monotherapy or present as comorbid for a variety of other disorders that either preclude the use of stimulants or produce a symptom complex that is resistant to monotherapy. Unfortunately, there are few agents well studied in combination with psychostimulants for patients with ADHD. The combination of psychostimulants with alpha2-adrenergic agonists may offer a complementary approach to treating such complex patients. The rationale for combination therapy is that the primary effects of stimulants and alpha2-adrenergic agonists are mediated by different but complementary mechanisms of action, emphasizing different neurotransmitter systems, which together modulate prefrontal cortex functioning. Although immediate-release clonidine and guanfacine have long been studied in ADHD, their usage has been limited by rapid absorption and clearance, negative side effects, and reduced efficacy compared with stimulants. New controlled-release formulations of the alpha2-adrenergic agonists have overcome some of these limitations, with recent clinical trials demonstrating their enhanced tolerability and effectiveness for treatment of ADHD in children and adolescents. Studies with each of these new formulations (ie, guanfacine extended release and clonidine hydrochloride extended-release tablets) in combination with psychostimulants have demonstrated that the addition of an alpha2-adrenergic agonist to psychostimulant therapy significantly enhances efficacy without compromising safety. This review will encompass the clinical study database for novel formulations of alpha2-adrenergic agonists, enabling the reader to appreciate their place in ADHD treatment as well as the potential utility of a combination approach with psychostimulants for patients with complex ADHD.