Strategies to achieve ambitious targets for reducing road accidents ( 34 ) have largely focused on engineering and technological advancements, the modification of occupational demands, and, to a lesser extent, human factors. These factors include stress and psychological states; sleep, fatigue, and alertness; and health status. Physical activity appears to influence all these human factors but has not previously been systematically considered as a direct or indirect risk factor for driver accidents. This chapter provides an overview, within an evidence-based framework, of the impact each of these human factors has on driver performance and risk of at-work road traffic accidents and then examines how physical (in)activity may moderate and mediate these relationships. Finally, we consider practical implications for work site interventions. The review aims to offer an evidence base for the deployment of resources to promote physical activity, manage stress, facilitate sleep, reduce fatigue, and enhance alertness to improve physical and psychological health among professional drivers.