The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.