Monoamine oxidase inhibitors (MAOIs), which ushered in the modern era of psychopharmacology in the 1950s, have remained useful in the treatment of depression despite important safety concerns, such as acute hypertensive episodes brought on by ingestion of foods with high-tyramine content. Experience has shown that MAOIs are broadly effective in the treatment of depressive disorders, including atypical, chronic, and double depressions. Newer selective and reversible inhibitors of the two forms of mitochondrial monoamine oxidase (MAO) enzymes, MAO-A and MAO-B, have been developed in an effort to improve the safety and tolerability of MAOIs. Selegiline, a selective inhibitor of MAO-B has been shown to be effective in the treatment of depression at higher oral doses where selectivity for MAO-B is lost. Transdermal delivery of selegiline bypasses first-pass metabolism and avoids impairment of the gastrointestinal barrier provided by MAO-A of the gastrointestinal mucosa. Studies have shown that the selegiline transdermal system (STS) does not significantly affect sensitivity to ingested tyramine, unlike tranylcypromine, which markedly increases sensitivity. STS has been found to be efficacious in the treatment of patients with major depression in placebo-controlled trials, without the need for dietary precautions. The favorable safety profile of STS should allow this MAOI to be a broadly used antidepressant drug.