Proinflammatory cytokines, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6, have multiple effects in the central nervous system (CNS) not strictly cytotoxic being involved in controlling neuronal and glial activation, proliferation, differentiation and survival, thus influencing neuronal and glial plasticity, degeneration as well as development and regeneration of the nervous system. Moreover, they can contribute to CNS disorders, including multiple sclerosis, Alzheimer's disease and human immunodeficiency virus-associated dementia complex. Recent results with deficient mice in the expression of those cytokines indicate that they are in general more sensible to insults resulting in neural damage. Some of the actions induced by TNF-α, and IFN-γ, including both beneficial and detrimental, are mediated by inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) production. NO produced by iNOS may be beneficial by promoting the differentiation and survival of neurons. IL-6 does not induce iNOS, explaining why this cytokine is less often involved in this dual role protection/pathology. Some of the proinflammatory as well as the neurotrophic effects of those cytokines also involve upregulation of cell adhesion molecules (CAM). Those apparently conflicting results may be reconciled considering that proinflammatory cytokines are involved in promoting the disease, mostly by inducing expression of CAM leading to alteration of the blood–brain barrier integrity, whereas they have a protective role once disease is established due to its immunosuppressive or neurotrophic role. Understanding the dichotomy pathogenesis/neuroprotection of those cytokines may provide a rationale for better therapeutic strategies.