Multiple sclerosis (MS) is defined as a chronic inflammatory disease of the central nervous system, which leads to focal inflammatory demyelinated lesions with secondary neurodegeneration. However, this concept has recently been challenged by several observations suggesting that in this disease neurodegeneration might occur independently of inflammation. Here, these new findings are critically discussed and evidence that active neurodegeneration in MS is invariably associated with inflammation is provided. The present review shows, however, that the inflammatory reaction is much more complex, as thought before, and that in the progressive stage of the disease it might become trapped in the central nervous system behind a repaired blood–brain barrier. Future therapeutic options for this disease are discussed on the basis of recent knowledge of the mechanisms of inflammation and neurodegeneration. (Clin. Exp. Neuroimmunol. doi: 10.1111/ j.1759‐1961.2009.00003.x, January 2010)