Despite the numerous reports on the role of tumor necrosis factor-alpha (TNF-alpha) in the brain neuropathology, very little is known about the mechanisms by which TNF-alpha may mediate neuroprotection. Different hypotheses pertain to the molecular and cellular effectors triggered by the activation of TNF receptors (TNFRI and TNFR2). They are focused on diminishing the production of nitric oxide and free radicals, alteration of excitatory amino acids neurotransmission, maintenance of neuronal calcium homeostasis and induction of neurotrophic factors synthesis. In this review all these data are summarized. Moreover, possible explanations for the inconsistent data concerning the TNF-alpha effect on neuron are discussed.