© 2015 Elsevier Inc. The Guidelines for Exercise in Multiple Sclerosis (GEMS) program is a randomized controlled trial (RCT) examining the feasibility and efficacy of a home-based exercise training program based on recent physical activity guidelines and principles of behavior change for improving symptoms and health-related quality of life (HRQOL) in adults with multiple sclerosis (MS). The primary aim is to assess program feasibility in the four domains of process (e.g., recruitment, retention, and adherence), resources (e.g., communication, staff requirements, and monetary costs), management (e.g., time and accuracy in data collection/entry, and reporting of adverse events) and scientific outcomes (e.g., safety, burden, participant feedback and efficacy/outcomes). The trial will recruit individuals with mild-to-moderate MS-related disability across the United States who will be randomized into intervention or waitlist control conditions. All participants will complete home-based assessments (including wearing an accelerometer for 7 days and completion of a questionnaire booklet) prior to and upon completion of the 4-month program. Participants in the intervention will receive a 4-month home-based exercise program emphasizing aerobic and resistance training. Participants will be provided with exercise equipment, a DVD, a manual and a log-book. The exercise program will be supplemented with periodic newsletters in the mail highlighting principles of behavior change, and video-chats with an exercise specialist to provide motivation and social accountability. This trial serves to inform development of Phase II and III RCTs which can determine the actual efficacy and effectiveness of home-based exercise based on the MS-specific physical activity guidelines for improving symptoms and HRQOL.