Although monoamine oxidase inhibitors (MAOIs) at one time represented the mainstay of therapy for major depressive disorder (MDD), the risk of acute hypertensive reactions following the ingestion of tyramine-rich foods and the consequent need to restrict dietary tyramine represent a barrier to their use. In this article, we present an overview of the efficacy and safety of a transdermal formulation of the MAOI selegiline for the treatment of MDD. Transdermal delivery of selegiline at the effective dose of 6 mg every 24 hours eliminates the need for a tyramine-restricted diet. Our emphasis on potential drug-drug interactions and contraindications should be useful to prescribers who counsel patients with MDD.