The development of new and more sensitive clinical outcome measures for research in multiple sclerosis (MS) has been fueled by the development of effective therapies. As such, active arm comparison studies that require more sensitive clinical outcome measures are now commonplace. The Kurtzke Expanded Disability Status Scale (EDSS), the most widely used measure of neurologic impairment in MS, is particularly designed for classifying patients with respect to disease severity but has been criticized for its noninterval scaling, emphasis on ambulation status, relatively reduced sensitivity in the mid and upper ranges of scores, and absence of adequate cognitive and visual components. In response to perceived difficulties with the EDSS, the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force has developed the Multiple Sclerosis Functional Composite (MSFC). The MSFC includes three components that yield objective and quantitative results: 1) the timed 25-ft walk, 2) the nine-hole peg test, and 3) the 3-second paced auditory serial addition test. This scale has the advantages of continuous scoring with a composite Z score, standardized protocols, and high degrees of reliability and validity. Candidate visual function outcome measures for the MSFC, including the low-contrast Sloan letter chart, are currently under investigation. In addition to measures of neurologic impairment, health-related quality of life (HRQOL) measures have gained increasing importance as clinical trial outcome measures. The MS Quality of Life Inventory, a disease-specific HRQOL measure, has been developed to capture self-reported neurologic dysfunction and the impact of MS upon activities of daily living. MS clinical trials of the future, particularly active-arm comparison studies, will require more sensitive clinical outcome measures such as the MSFC. Measures of visual function and HRQOL should also be incorporated to capture the broad scope of neurologic impairment and disability in MS populations.