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Optical coherence tomography (OCT) has made possible the structure–function correlations that uniquely characterize the afferent visual pathway as a model for understanding multiple sclerosis (MS) and for developing new treatments. During the past decade, OCT measures of retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCL + IPL) thickness have evolved from being a means to validate visual function tests, such as low-contrast letter acuity, to provide a window on the axonal and neuronal loss that are now widely recognized as contributors to permanent visual dysfunction in MS. Although acute optic neuritis (ON) leads to thinning of the RNFL by 20%–40% within 3 months after a single episode, thinning of the RNFL and GCL + IPL occur over time in MS eyes even in the absence of an acute ON history. As such, OCT and its functional and patient-reported correlates of low-contrast acuity and vision-specific quality of life (QOL) have now been incorporated into MS clinical trials. Results of an ongoing, phase 2 trial of a remyelinating agent that uses acute ON as a model for assessing therapeutic efficacy will define even further the important role for OCT in documenting structural changes as we move forward from clinical trials to clinical use.