Although conventional magnetic resonance imaging (cMRI) is widely used for diagnosing multiple sclerosis (MS) and monitoring disease activity and evolution, the correlation between cMRI and clinical findings is far from strict. Among the reasons for this "clinical-MRI paradox," a major role has been attributed to the limited specificity of cMRI to the heterogeneous pathological substrates of MS and to its inability to quantify the extent of damage in the normal-appearing tissue. Modern quantitative MRI techniques have the potential to overcome some of the limitations of cMRI. Metrics derived from magnetization transfer and diffusion-weighted MRI enable one to quantify the extent of structural changes occurring within and outside macroscopic MS lesions with increased pathological specificity over cMRI. Magnetic resonance spectroscopy can add information on the biochemical nature of such changes, with the potential to improve significantly our ability to monitor inflammatory demyelination and axonal injury. Finally, functional MRI might provide new insights into the role of cortical adaptive changes in limiting the clinical consequences of white-matter structural damage. This review outlines the major contributions given by MRI-based techniques to the diagnostic work-up of MS patients, to the understanding of the pathobiology of the disease, and to the assessment of the effects of new experimental treatments.