Multiple sclerosis (MS) has been classically regarded as a white matter disease. However, recent histopathological studies have convincingly shown that grey matter regions are also heavily affected. Grey matter damage starts early in the disease and substantially affects clinico-cognitive functioning. Detection of cortical grey matter lesions by use of standard MRI techniques has proved challenging, and more advanced techniques are needed. At present, the causes of grey matter damage are unclear. We review several exciting new hypotheses on grey matter pathogenesis, including meningeal inflammation as a cause of subpial cortical damage, but also selective vulnerability of neuronal subpopulations, growth factor dysregulation, glutamate excitotoxicity, mitochondrial abnormalities, and the "use-it-and-lose-it" principle. These hypotheses remain to be validated over the coming years, and could substantially affect our current views on MS pathogenesis.