This chapter examines the efficacy of conventional and second generation monoamine oxidase inhibitors (MAOIs) in treatment-resistant depression. The three classical monoamine oxidase inhibitors used at present are phenelzine, tranylcypromine, and isocarboxazid. The new reversible and selective monoamine oxidase A inhibitors (RIMAs) such as moclobemide, brofaromine and toloxatone have fewer adverse effects and, because MAO-B is still available for tyramine degradation, there is no need for any no diet restrictions. Lithium carbonate is an effective potentiator of tricyclic antidepressants (TCAs). At present, there are no comparative studies evaluating the safety and efficacy of lithium potentiation of RIMAs. RIMAs offer a relatively safer option which can benefit the treatment-resistant patient. The first-line treatment for treatment-resistant depression should be a specific serotonin reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline, and fluvoxamine, or a serotonin and norepinephrine reuptake inhibitor (SNRI) such as venlafaxine.