Diffusion tensor (DT) MR imaging is able to detect and quantify multiple sclerosis (MS)–related tissue damage within and outside T2-visible lesions. DT MR imaging has also been shown to be sensitive to the evolution of MS damage over time and to provide in vivo correlates of MS clinical severity and paraclinical markers of long-term disease evolution. Recent developments of DT MR imaging postprocessing techniques, such as tractography and voxelwise analysis, are likely to improve our understanding of the mechanisms associated with the accumulation of disability in MS. Important issues remain to be addressed, such as a detailed definition of the actual features underlying diffusion changes in MS and the potential of the technique in the differential diagnosis of MS.