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Objective: The singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder from all other psychiatric disorders. Despite the fact that it is a core aspect of the clinical presentation of bipolar disorder, the neurobiology of the switch process is still poorly understood. In this review, we summarize the clinical evidence regarding somatic interventions associated with switching, with a particular focus on the biologic underpinnings presumably involved in the switch process. Data Sources: Literature for this review was obtained through a search of the MEDLINE database (1966–2008) using the following keywords and phrases: switch, bipolar disorder, bipolar depression, antidepressant, SSRIs, tricyclic antidepressants, norepinephrine, serotonin, treatment emergent affective switch, mania, hypomania, HPA-axis, glucocorticoids, amphetamine …