Multiple sclerosis is known to be an inflammatory demyelinating disease characterized mainly by multifocal areas of white matter lesions. Recently, cortical lesions and brain atrophy have emerged as new pathological markers of disease progression. Brain tissue loss can now be easily and reproducibly detected and quantified by MRI, which has led to an increasing amount of research correlating brain tissue loss with other MRI markers, such as white matter lesions, and to clinical disabilities (motor or cognitive), in order to assess its clinical relevance. In this review, we summarize the different MRI-based methods used to quantify whole and regional brain atrophy, and discuss the relevance of brain atrophy in MS through its relationship with characteristic brain lesions, disability and cognition. Lastly, we emphasize the role of brain atrophy in different phenotypes of MS. According to this review of the current literature, the grey matter (GM) atrophy is now well-established in MS and has been found to be strongly associated with clinical and cognitive deterioration. This GM volume loss is characterized by a focal atrophy in the deep grey nuclei but also by diffuse cortical atrophy. Phenotypic variation can be associated with different degrees and regional location of brain atrophy but more investigations are necessary to specify the discrepancies against brain atrophy between the different forms of the disease.