Activated glial cells are capable of generating various inflammatory mediators, including cytokines, nitric oxide and reactive oxygen species. These potentially neurotoxic molecules have been suggested to play a role in the etiology and development of depression. Accumulating evidence indicates that antidepressants have inhibitory effects on inflammatory activation of glial cells and confer neuroprotection under neuropathological conditions. Such efficacy of antidepressants appears to depend on suppressing microglial production of inflammatory substances and up-regulating both astrocytic secretion of neurotrophins and astrocytic glutamine synthase, which converts neurotoxic glutamate into non-toxic glutamine. Therefore, glial cells, both as source and target of inflammatory molecules, may represent a potential promising target involved in the pathophysiology of depression. Moreover, antidepressants have the possibility to be useful treatment, not only for depression, but for a broad spectrum of neuroinflammatory and neurodegenerative disorders where the pathogenesis is associated with glial activation.