Tumor necrosis factor (TNF) has been implicated in the pathogenesis of various central nervous system diseases with an inflammatory component. Elevated TNF levels were observed in animal models of motor neuron disease (MND), and activation of the TNF system has been reported in patients with amyotrophic lateral sclerosis (ALS). The easy availability of scientific reports to the layman through the web, often based only on the abstracts, has prompted many patients to ask whether anti-TNF therapy might be beneficial in ALS. This review discusses the possible role of TNF in motoneuronal degeneration. Although TNF is mostly regarded as neurotoxic cytokine, there are reports of a neuroprotective and neurotrophic action. Studies with animal models of ALS are not sufficient to show whether TNF has a pathogenic or a protective role in MND though anti-TNF antibodies have shown protective effects in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). On the other hand, while TNF-deficient mice are protected from EAE, anti-TNF antibodies worsen the disease in MS patients, suggesting caution in extrapolating preliminary basic studies to the patient.