Methylphenidate (MPH) is very effective in the treatment of attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Blockade of the dopamine transporter is thought to produce the therapeutic effects of MPH by increasing concentrations of dopamine within the central nervous system. Although MPH is a racemic compound composed of a 50:50 mixture of dexmethylphenidate (d-MPH) and l-methylphenidate (l-MPH), animal and human studies have confirmed that the d-MPH isomer is responsible for the pharmacodynamic effect of MPH. Positron emission tomography scan images in rats and baboons treated with radiolabeled MPH have confirmed the specificity of the d-isomer and lack of specific binding of the l-isomer. Clinical studies evaluating d-MPH in both children and adults with ADHD have confirmed the efficacy and safety of the stereoselective isomer in the treatment of ADHD. The immediate-release formulation of d-MPH produces effects similar to d,l-MPH in children as measured by teacher-assessed Swanson, Nolan, and Pelham scores, Math test results, Conners Teacher and Parent Rating Scales, Attention Deficit Disorder Rating Scale, Global Assessment of Functioning scale, and Clinical Global Impression-Improvement scores. An extended-release formulation with a rapid onset of action and sustained benefit over 12 hours provides similar clinical benefit in children and adults with ADHD with excellent tolerability and the advantage of once-daily dosing.