OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and tolerability of reboxetine in the treatment of major depressive illness. DATA SOURCES: A MEDLINE search restricted to English-language literature was conducted (1966 to July 1999). Abstracts and posters presented at meetings were also reviewed. DATA EXTRACTION/STUDY SELECTION: Studies currently available were conducted in Europe. Data from clinical trials were reviewed to gather information specific to efficacy analysis, pharmacokinetic parameters, tolerability profiles, and drug-drug interactions. Information on reboxetine was compared with other antidepressant therapies when appropriate data were available. DATA SYNTHESIS: Reboxetine is a selective norepinephrine reuptake inhibitor shown to be an effective agent in the treatment of major depressive illness. In clinical trials, reboxetine was effective in decreasing mean total scores of the Hamilton Rating Scale for Depression in adult populations. Improvements were similar between reboxetine and desipramine and imipramine, as well as fluoxetine. Reboxetine is relatively well tolerated, with insomnia, sweating, constipation, and dry mouth being commonly reported adverse events. Hypotension and urinary hesitancy occur at lower rates than with the tricyclics, and compared with fluoxetine, reboxetine is associated with lower rates of nausea, somnolence, and diarrhea. Dosage adjustments may be appropriate in elderly patients and those with renal and hepatic impairment. CONCLUSIONS: Reboxetine has received two letters of approval from the Food and Drug Administration for the treatment of major depression in adults. Upon completion of an additional US clinical study, reboxetine is likely to become a first-line agent in the management of depressive illness and a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants.