The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1ß, TNF-α and IFN-γ seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic-pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system.