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Purpose of review The article provides an overview of the importance of whole-brain atrophy in multiple sclerosis (MS) and proposes steps that would be necessary prior to incorporating whole-brain volume measurements into routine clinical practice. Recent findings Whole-brain atrophy is clinically relevant, present early in the disease, and measureable in a reproducible manner using MRI. Several of the currently available approved disease-modifying therapies can slow the rate of whole-brain atrophy at the group level. As such, clinicians may want to use whole-brain volume measurements for clinical decision-making. Summary Despite its relevance and face validity, several steps must be taken before whole-brain volume measurements are ready to be incorporated into clinical practice, including the adoption of a standardized MRI protocol for MS, the establishment of a gold-standard image postprocessing software to measure whole-brain volume, and the development of specific statistical methods to translate whole-brain volume measurements into clinically relevant metrics at the individual level. As neurodegeneration becomes the focus of MS research worldwide and the likely target of the next generation of disease-modifying therapies, MRI metrics associated with neurodegeneration will be critically important to monitor disease progression and treatment response at the group and individual levels.