Monoamine oxidase inhibitors (MAO-I) are the first drugs of antidepressant classes discovered. Phenelzine is a worldwide prescribed MAO-I, studied in a variety of mood and anxiety disorders. Purpose of the present paper is to critically review the results reported in the scientific international literature focusing on efficacy and safety of phenelzine in clinical psychiatric practice, in order to achieve a better understanding of the relationship between pharmacological data, therapeutic approach and side or adverse effects. We performed a careful PubMed (1980-2012) search on clinical pharmacology and clinical use of phenelzine in various psychiatric disorders. We reported our findings discussing separately clinical pharmacology data and systematic controlled, randomised and not randomised, clinical studies.