An estimated 2.5 million people worldwide are living with multiple sclerosis (MS), and this disease may be increasing in prevalence. MS is a disease of the central nervous system that is associated with heterogeneous symptoms and functional consequences, and the current first-line disease-modifying therapies often become ineffective later in the disease. There is increasing evidence for the benefits of physical activity (PA) in people with MS, but this population is generally physically inactive and sedentary. We proposed 10 research questions to guide future research on PA and MS: (1) Is PA an MS disease-modifying behavior? (2) What are the benefits of PA among people with MS? (3) What is the optimal PA prescription for people with MS? (4) What are the safety issues with PA in people with MS? (5) What characteristics of people with MS modify the benefits of PA? (6) What variables explain participation in PA among people with MS? (7) What are effective behavioral interventions for PA change in people with MS? (8) How do we translate PA research into clinical MS practice? (9) What is the role of sedentary behavior in people with MS? And (10) what is the optimal measurement of PA in people with MS? These questions are critical for informing our understanding of the short- and long-term consequences of PA in MS as well as for identifying approaches for promoting and sustaining PA in MS. Addressing these questions may greatly improve the lives of people with this chronic disease.