This article is a clinical guide which discusses the state-of-The-Art usage of the classic MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI-prescribers. It discusses indications, drug drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (over 70 international expert129 endorsers), based on six decades of experience, for the recommendations herein exposited. They are based on empirical evidence and on expert opinion this guide is presented as a new specialist131 consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to ECT whilst taking account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some TCAs. It also illustrates the straightforward bridging methods that may be used to transition simply and safely from other antidepressants to MAOIs.