Besides focal white matter lesions, multiple sclerosis brain tissue also displays abnormalities in the gray matter and the normal-appearing white matter. Recent advances in magnetic resonance imaging studies of both types of tissue are discussed. Herein, normal-appearing white matter abnormalities are being found in quantitative magnetic resonance investigations, consistent with a limited degree of axonal damage and/or demyelination, and an increase of glial cells, but the specific nature of the histopathological changes underlying the quantitative magnetic resonance abnormalities remains unclear. Gray matter studies have demonstrated that much of the disease process remains undetected by conventional magnetic resonance imaging. Although newly developed techniques, such as 3D double-inversion recovery, may greatly improve detection of cortical pathology, it remains important to investigate the resultant effects on the cortical tissue alongside this, by studying integrity of normal-appearing cortical tissue through quantitative magnetic resonance studies, as well as the net neurodegenerative effect through measurements of cortical thickness and cortical atrophy (rates). To improve our understanding of normal-appearing white and gray matter changes, their mutual relations, and their relations to clinical changes, further in vivo magnetic resonance imaging studies are required. Specifically, it is proposed that more spatially specific investigations, ideally utilizing subject-specific anatomical information from, for example, diffusion fiber-tracking techniques, could be used to gain more insight into the relations between normal-appearing white matter changes, cortical changes, magnetic resonance visible focal-lesions, and physical and cognitive deficits.