Initially introduced in the 1950s for treating depression, monoamine oxidase (MAO) inhibitors were gradually abandoned, mainly owing to their potential for drug-drug and drug-food interactions, the most widely known being with tyramine-containing food (the 'cheese' effect). Since then, more selective MAO-A or MAO-B inhibitors have been developed with substantially reduced risks, and have been approved for the treatment of depression and Parkinson's disease, respectively. Recent research suggests that some of these drugs also have neuroprotective properties, while preclinical evidence expands the spectrum of potential indications to heart failure, renal diseases and multiple sclerosis. In this article, the authors review the relevance of MAO isoforms to disease, and they also outline current research and development efforts in this class of drugs, including newer multipotent compounds.