Although the correlations between magnetic resonance imaging (MRI) findings and long-term disease evolution range from poor to moderate', conventional pre- and post-contrast MRI provides sensitive and reliable measures to monitor multiple sclerosis (MS) activity over time. The application of non-conventional techniques, such as magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI), can increase the pathological specificity of MRI findings and, as a consequence, improve the relationship with the clinical evolution of the disease. These techniques also enable us to quantify the subtle abnormalities occurring in the so-called normal-appearing white matter, thus allowing to achieve a more accurate assessment of MS burden. Some of the aforementioned techniques have already shown their value for assessing MS dynamics, whereas other still need to go through a more complete validation process prior to any extensive clinical application in MS. The use of multiparametric MRI approaches, including both conventional techniques and new methods able to assess the macro- and microscopic disease burden and to characterize the individual lesion intrinsic nature, should improve our ability to study in vivo the pathology of MS.