Although our understanding of multiple sclerosis (MS) has grown exponentially in the past century and a half, there is still some divergence between physicians’ perceptions of effects of MS on patients and those of the patients themselves. This article examines current practices in MS assessment and clinical trial design, highlighting certain deficiencies associated with commonly used measurement techniques (e.g., the Expanded Disability Status Scale and MRI) that are reflective of these discrepancies. In particular, the authors note that there is only minimal clinical awareness of the effects of MS on patient quality of life (QoL). We posit that QoL elements including impaired cognition, fatigue, pain, a variety of visual disturbances, depression, and degrading social function may have at least as much impact on people with MS as ambulatory issues. And because QoL measures often do not correlate with Expanded Disability Status Scale or MRI findings, we recommend that QoL be assessed independently. Various validated measures do exist to assess QoL elements, which are outlined here, along with thoughts on how to incorporate these into regular patient management visits. Ultimately, we believe that expanding on the traditionally accepted definitions of “functionality” and “efficacy” will allow for the adoption of a more holistic picture of MS and its impact.