Adrenergically active drugs used for the treatment of attention-deficit/hyperactivity disorder (ADHD) include the alpha-agonists, monoamine oxidase inhibitors, tricyclics and the selective noradrenergic re-uptake inhibitors. In addition to a longer duration of treatment effect than the predominantly dopaminergic psychostimulant drugs, a theoretical advantage of the adrenergically active drugs is a lesser tendency to aggravate common comorbidities of ADHD, such as anxiety, obsessionality, depression and tics. Nevertheless, adrenergically active drugs have always been considered second-line treatments to the psychostimulant drugs. No study has demonstrated superiority of adrenergically active drugs over the psychostimulants in reducing the core symptoms of ADHD, although several small trials have suggested 'equivalence'. The case for superiority of the adrenergically active drugs over psychostimulants in alleviating comorbid symptoms remains largely unproven, as there have been few comparative trials. Safety data have favoured the psychostimulant drugs. The advantage of once daily or morning and evening dosing of the adrenergically active drugs has been diminished since the introduction of sustained release preparations of methylphenidate and amphetamine. Although adrenergically active drugs may be the preferred treatment in the presence of severe comorbidity, for the most part they remain second-line treatment for ADHD.