By studying exercise and performance in hand-cycling in both activities of daily living and in Paralympic sport settings, new insights can be gained for rehabilitation practice, adapted physical activity, and sports. This review looks into the pros and cons of hand-cycling in both rehabilitation and optimal sports performance settings as suggested from the current—but still limited—scientific literature and experimentation. Despite the limited evidence-base and the diversity of study approaches and methodologies, this study suggests an important role for hand-cycling during and after rehabilitation, and in wheeled mobility recreation and sports. An approach that combines biomechanical, physiological, and psychosocial elements may lead to a better understanding of the benefits of hand-cycling and of the fundamentals of exercise in rehabilitation, activities of daily living, and sports.