Sleep deprivation (SD) is the most widely documented rapid-onset antidepressant therapy, targeting the broadly defined depressive syndrome. Although SD responses are transient, its effects can be sustained by concomitant medications (e.g., selective serotonin reuptake inhibitors and lithium) and circadian-related interventions (e.g., bright light and sleep phase advance). Thus, considering its safety, this technique can now be considered among the first-line antidepressant treatment strategies for patients affected by mood disorders. SD is a complex intervention and it should be considered multi-target in nature. Thus, the mechanisms explaining its antidepressant effect can be looked for on many levels, involving not only monoaminergic mechanisms but also sleep homeostatic and circadian mechanisms, glutamatergic mechanisms and synaptic plasticity.