The development of effective and safe antidepressant medications is ongoing, and driving studies are critical to assess a drug's safety. The current review summarizes the effects of a sedating effective antidepressant, mirtazapine, on driving ability, and its potential to serve as positive control drug in future driving studies. Three on-road driving studies and four driving simulator studies of mirtazapine were identified. The studies, conducted in healthy volunteers, showed a significant dose-dependent driving impairment, the first day following bedtime administration of mirtazapine. The magnitude of impairment after a single dose of 15 mg or 30 mg mirtazapine was comparable to that observed with a blood alcohol concentration of 0.05%, the legal limit for driving in many countries. After 1 or 2 weeks of daily treatment with mirtazapine, partial tolerance developed to mirtazapine's effects on driving. Driving studies conducted in patients were less informative, as the effect on driving caused by mirtazapine was obscured by a drug–disease interaction and increased variability in patient groups. In conclusion, mirtazapine is useful as positive control drug to assess the potential effects of new antidepressant drugs on driving. Studies in normal healthy volunteers are more sensitive to drug effects than studies in patient populations.