Due to its sensitivity in the detection of focal white matter (WM) lesions, MR imaging has become a paraclinical tool central to diagnosing multiple sclerosis (MS) and monitoring its evolution. Despite this, the correlation between patients’ clinical status and conventional MR imaging measures is weak to moderate. Quantitative MR imaging–based techniques, such as magnetization transfer and diffusion tensor imaging, have a higher specificity toward the heterogeneous pathologic substrates of MS than MR imaging. This article discusses the main insights derived from the application of such MR imaging–based techniques to define MS pathophysiology and to quantify the progressive accumulation of structural damage in the central nervous system. © 2016 Elsevier Inc.