Magnetic resonance imaging (MRI) is sensitive to focal multiple sclerosis (MS) lesions. For this reason, conventional MRI measures of the burden of disease derived from dual-echo, fluid-attenuated inversion recovery and postcontrast T1-weighted sequences are regularly used to monitor disease course in patients with confirmed MS and have been included in the diagnostic workup of patients in whom MS is suspected. Other quantitative magnetic resonance (MR)-based techniques with a higher pathological specificity (including magnetization transfer-MRI, diffusion tensor-MRI, and proton MR spectroscopy) have been extensively applied to measure disease burden within focal visible lesions and in the normal-appearing white matter and gray matter of MS patients at different stages of the disease. These methods, combined with functional imaging techniques, are progressively improving our understanding of the factors associated with MS evolution. More recently, the application of new imaging modalities capable of measuring pathological processes related to the disease that have been neglected in the past (eg, iron deposition and perfusion abnormalities) and the advent of high- and ultrahigh-field magnets have provided further insight into the pathobiological features of MS. After a brief summary of the main results obtained from the established and emerging MR methods, this review discusses the steps needed before the latter become suitable for widespread use in the MS research community.