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Quant Imaging Med Surg 2020;10(2):527-532 | http://dx.doi.org/10.21037/qims.2020.01.04 Over more than 35 years, advances in magnetic resonance imaging (MRI) techniques and analysis have fundamentally impacted both diagnostic criteria and treatment algorithms for multiple sclerosis (MS), a potentially disabling neurologic condition that affects nearly 1 million people in the United States alone (1). MS results in multi-focal lesions in the gray and white matter of the central nervous system, histopathologically characterized by varying degrees of inflammation, demyelination, axonal loss, gliosis and remyelination. As the disease progresses, the formation of new lesions becomes less frequent and a “degenerative” phase of diffuse axonal injury and accelerated brain atrophy gradually becomes apparent. Quantitative MRI-based lesion metrics are now routinely incorporated as primary or secondary endpoints in Phase 2 and 3 clinical trials of disease modifying therapies (DMT) for MS. Similarly, MRI detection of gadolinium-enhancing, new T2 or enlarging T2 MS lesions is an established biomarker of ongoing brain inflammation that commonly drives treatment escalation in clinical practice, even in the absence of discernable relapse. The widespread availability of highly accurate, quantitative lesion metrics will further drive individualized approaches in an increasingly complex therapeutic environment. Despite these advances, sub-clinical MRI-based biomarkers of disease progression or neurodegeneration remain relatively underdeveloped; and are lacking in clinical practice. At the group level, MRI-detected whole brain atrophy (WBA) associates strongly with disability progression (2-5) and is a common secondary endpoint in MS clinical trials. However, WBA measurement in individual patients is confounded by measurement error and biological fluctuations in brain volume; requires expert neuroimaging analysis skills; and is yet to be validated as a clinical-decision making tool. When highly effective anti-inflammatory DMT are commenced in relapsing, active MS, new lesion formation is rare and WBA rates may return to the normal range. The effect of these therapies on clinical outcomes in patients with later, progressive forms of the disease is modest, though some gains have been made in recent clinical trials of ocrelizumab (6) and siponimod (7) in primary and secondary progressive MS cohorts respectively. Over the next decade, a new era of neuroprotective and remyelinating therapies is expected to complement the existing armamentarium of anti-inflammatory DMT, with promising early studies of agents such as biotin (8) and clemastine (9), among others. The rapidity with which novel mechanisms of neurodegeneration and molecular obstacles to remyelination are being identified (and translated to Phase 2 clinical trials) has exposed a critical unmet need for robust, in-vivo MRI biomarkers for predicting and monitoring Editorial Commentary