The tumor necrosis factor-α (TNF-α) system is involved in several regulatory processes within the body. The action of TNF-α is mediated by the two cell surface receptors TNF-R p55 and TNF-R p75. Soluble TNF receptors (sTNFRs) are soluble variants of the extracellular domains of their membrane-bound form. To assess the activity of the TNF-α system in patients suffering from disorders of the central nervous system - such as depression, narcolepsy, multiple sclerosis, Alzheimer ’ s and Parkinson ’ s disease - and during psychopharmacological therapy, several studies investigated plasma levels of TNF-α, TNF-R p55 and TNF-R p75 and the local concentration of TNF-α in the brain. It could be shown that an activation of the TNF-α system might promote the development of psychiatric or neurological symptoms or disorders. Additionally, endocrine changes associated with brain disorders may lead to alterations of the TNF-α system. Psychotropic drugs influence the TNF-α system by normalizing the HPA axis changes associated with psychiatric diseases, and inducing weight gain and liver damage. Several side effects of psychotropic drugs resemble brain disorders in which the TNF-α system plays an important pathogenetic role. One could wonder whether these side effects may at least in part be mediated by an activation of the TNF-α system.