Although current medication therapies ameliorate ADHD behavioral symptoms, problems with inadequate response or tolerability are common. Most perplexing, in consideration of ADHD-related cognitive deficits and in spite of several hundred studies demonstrating acute behavioral response to stimulants, is the failure of many decades of research to demonstrate long-term, stimulated-related enhancements in learning. This manifest inadequacy of current therapies highlights the potential importance of developing treatments that specifically remediate executive function deficits as an important path to improve outcome. Neurochemical influences on cognitive functions in ADHD are complex. The over-arching premise of this project is that optimal behavioral and cognitive responses are possible with treatments that robustly enhance both dopamine (DA) and norepinephrine (NE). Our goal is to test the short-term efficacy of a combination pharmacotherapy, derived from translational research and clinical observations, against standard stimulant monotherapy on both symptom and cognitive endpoints. In addition, a novel aspect of the study will be to test prospectively whether a dual benefit on both behavior and cognition predicts clinically significant improvements in learning over longer-term treatment. Lastly, based upon our preliminary data and hypothesized mechanisms of treatment response, the proposed study will examine the potential of electroencephalography (EEC) in predicting optimal long-term benefit. The clinical trial will enroll 180 children and adolescents with ADHD-Combined Type in an active-controlled randomized parallel group study testing the comparative efficacy of guanfacine (GUAN), methylphenidate (MPH), and combination GUAN/MPH on ADHD symptoms and clinical response rates. Improvements in cognition during the acute treatment phase will predict greater academic achievement over the 12 month maintenance period. The project will represent an initial scientific investment in a new phase of translational treatment research on cognition in developmental psychopathologies. The designs and methodology tested in the proposed trial will serve as a platform for testing other interventions.