Conventional magnetic resonance imaging (cMRI) is widely used for diagnosing multiple sclerosis (MS) and as a paraclinical tool to monitor disease activity and evolution in natural history studies and clinical trials. However, the correlation between cMRI and clinical findings is far from strict, and such a discrepancy is even more evident when moving from the setting of large-scale studies to the management of individual patients. Among the reasons for this "clinical-MRI paradox" is the limited specificity of cMRI to the heterogeneous pathologic substrates of MS and its inability to quantify the extent of damage in the normal-appearing tissues. Modern quantitative MR techniques have the potential to overcome some of the limitations of cMRI. Although the application of modern MR techniques is changing dramatically our understanding of how MS causes irreversible disability, their use for clinical trial monitoring and clinical practice is still very limited. Whereas there is increasing perception that modern quantitative MR techniques should be more extensively employed in clinical trials to advance the understanding of MS and derive innovative information, their use in clinical practice should still be regarded as premature.