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An inability to self-regulate negative emotions appears to play a pivotal role in the genesis of major depressive disorder. This inability may be related to a dysfunction of the neural circuitry underlying emotional self-regulation. This functional magnetic resonance imaging study was conducted to test this hypothesis. Depressed individuals and controls were scanned while they attempted to voluntarily down-regulate sad feelings. The degree of difficulty experienced during down-regulation of sadness was higher in depressed individuals. Furthermore, there was greater activation in the right dorsal anterior cingulate cortex, right anterior temporal pole, right amygdala, and right insula in depressed individuals. These results suggest that emotional dysregulation in major depressive disorder is related to a disturbance in the neural circuitry of emotional self-regulation.