Reduced physical activity is a consequence of progressive neuromuscular diseases, which negatively impacts quality of life and health outcomes. Reduced functional muscle mass is common to all neuromuscular diseases and results from both atrophy of disuse secondary to a sedentary lifestyle and muscle degeneration secondary to the disease itself. This review summarizes current concepts relating to the impact of reduced physical activity on health and fitness, potential determinants of physical activity levels in neuromuscular diseases, and new approaches to the quantitative measurement of physical activity in neuromuscular disease populations. The interrelationship of disease pathophysiology, impairment, functional limitation, disability, and societal limitation in the determination of physical activity in the community in neuromuscular diseases is discussed using Duchenne muscular dystrophy as an example. Future research pertaining to physical activity in neuromuscular disease will need to focus on the development of scientifically based recommendations concerning optimal exercise approaches with both disease-specific and general guidelines.