Coincident with and in part fueling advances in diagnostic nosology and drug development, the recent resurgence of interest in monoamine oxidase inhibitors (MAOIs) is reviewed. Accidentally discovered nearly 40 years ago as the first true antidepressants, the MAOIs soon fell into disfavor due to concerns about toxicity and seemingly lesser efficacy compared with the newer tricyclic compounds. Now that we have better understanding of the nature of the hypertensive and hyperpyrexic interactions of MAOIs with other substances, these medications have assumed a role in the treatment of nonendogenous depressive and anxiety syndromes, especially in operationally defined "atypical depression." The discovery of two MAO isoenzymes has resulted in a new generation of selective inhibitors in the search for enhanced efficacy (i.e., clorgyline) or safety (i.e., l-deprenyl). Most promising is the emerging class of reversible selective MAO-type A inhibitors, such as moclobemide, which combine antidepressant potency with freedom from the risk of dangerous tyramine-type adverse interactions.