Multiple randomized double-blind placebo-controlled trials have shown that botulinum toxin A (BoNT/A), when injected into the frown musculature, is an antidepressant. This review outlines the conceptual narrative behind this treatment modality, starting with theory developed by Charles Darwin. We develop the concept of emotional proprioception and discuss how the muscles of facial expression play an important role in relaying valenced information to the brain’s emotional neuroanatomical circuit. We review the role of facial frown musculature as the brain’s barometer and transmitter of negatively valanced emotional information. The direct connections between the corrugator muscles and the amygdala are reviewed, and these provide a neuroanatomical circuit that is a logical target for treatment with BoNT/A. The centrality of amygdala dysfunction in the pathogenesis of many psychiatric disorders, and the evidence that BoNT/A modulates amygdala activity, provides the mechanistic link between BoNT/A and its antidepressant activity. Animal models of BoNT/A’s antidepressant effects confirm the evolutionary conservation of this emotional circuit. The clinical and theoretical implications of this evidence, as it relates to the potential treatment of a broad range of psychiatric disorders by BoNT/A, is discussed. The ease of administration, long duration, and favorable side effect profile of this therapy is reviewed in the context of existing antidepressant treatments.