The authors provide clinical suggestions for optimizing the use of atomoxetine in practice. Atomoxetine is a highly specific norepinephrine inhibitor that was developed for the treatment of attention-deficit/hyperactivity disorder (ADHD) in all age groups. In clinical trials, it has a slightly lower effect size (0.2) than stimulants, but these studies exclude patients who are stimulant nonresponders as well as patients with comorbidities that constitute a relative contraindication to stimulants, such as tics, anxiety and substance use. If these common comorbid conditions were included, the outcome of the studies might have been different. Side effects, such as nausea, vomiting and stomach ache, may be mitigated by giving the medication on a full stomach, while sedation may be mitigated by giving the medication in the evening. Time course to response for atomoxetine is slower than that of stimulants, but a positive outcome provides for more consistent coverage over a 24-h period. Atomoxetine may be combined with stimulants to optimize full-day coverage with a booster effect on symptoms during the day. No studies to date examining real-life effectiveness outcomes of atomoxetine versus stimulants have examined quality of life, functioning, impact on comorbidity and long-term persistence with medication.