Gray matter demyelination is frequent and extensive in most patients with multiple sclerosis (MS) and has recently received much attention in neuropathologic and imaging studies. Gray matter lesions show distinct pathologic features that make their detection difficult with conventional imaging techniques. Thus, despite their high prevalence, their impact on clinical symptoms has not been defined well so far. This review focuses on recent information from pathologic and imaging studies and summarizes our current knowledge on cortical pathology derived from human and experimental studies.