Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course. Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression. It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.