Through unintentional discovery, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were the first antidepressant classes to be used clinically and have been widely available for over half a century. From the 1950s to the 1980s, these two classes of antidepressants were the sole antidepressant tools available to psychiatrists. With the advent of the selective serotonin reuptake inhibitors (SSRIs) in the 1980s and 1990s, the prescribing of the MAOIs and TCAs has fallen significantly worldwide. In this chapter, we take a closer look at the arc of MAOI discovery and clinical use, and how these two classes of drugs compare to each other. This is important because relatively few studies compare these older classes of drugs to the newer classes of antidepressants. Finally, we argue that TCAs, and particularly MAOIs, should continue to play an important role in the modern treatment of depression, especially in the treatment-resistant patient.