Monoamine oxidase inhibitors (MAOIs) were among the first class of agents introduced for the treatment of depression. However, they have fallen out of favor among clinicians over the years, due mostly to an unfavorable safety profile, the need for restrictive dietary prohibitions, and the fear of hypertensive crisis. The development of a novel, transdermal MAOI system now offers clinicians an additional option for managing patients with unipolar, bipolar, atypical, and treatment-resistant depression.