Treatment-resistant depression (TRD) may be implicated in 33–57% of depression cases. The currently available effective treatments include electroconvulsive therapy (ECT) or augmentation of serotonin selective reuptake inhibitors (SSRIs) with antipsychotics. ECT and antipsychotics are both associated with safety and tolerability concerns. Depression is hypothesized to result from a dysregulation of monoamine neurotransmitters, although the source of the dysregulation has been unclear. However, recent studies have revealed that an enzyme that degrades the neurotransmitters, known as monamine oxidase-A (MAO-A), may be overactive in patients with depression. Thus, treatments for depression that modulate MAO-A could act upstream relative to current antidepressant treatments. Monoamine oxidase inhibitors (MAOIs) can be highly effective therapeutic agents for depression and some anxiety disorders. Some evidence suggests that MAOIs may act by reversing excessive neurotransmitter depletion within the neuron and the synapse. MAOIs tend to be underutilized in clinical practice, due in part to misinformation and mythology about their dietary and drug interactions. The new class of reversible monoamine oxidase inhibitors (RIMAs) has shown efficacy in depression, with safety and tolerability comparable to SSRIs. This article discusses recent progress in RIMAs toward the treatment of TRD. Dietary and drug interactions of MAOIs will be covered, as well as guidelines for integrating these agents into clinical practice.