Fatigue for many people has become an everyday occurrence, particularly due to the demands associated with work hours, lifestyle, work family balance, travel, and commuting. Within a workplace, hazards such as fatigue require particular consideration and risk mitigation strategies to ensure a safe workplace. One area requiring increased attention within the work environment is fatigue within the work-driving context. Many people as part of their workday drive for work, and this activity has been identified as a high-risk work activity due to the significant injuries and fatalities attributed to work crashes. The demands associated with work and business and the geographical size of Australia can result in increasing amounts of time spent behind the wheel. Fatigue is a contributing factor to workplace crashes. Fatigue is a product of both physiological and environmental properties and has a significant impact on an individual’s driving ability resulting from decreased psychological functioning, delayed reaction time, poor decision-making, and reduced attentiveness. Transport industry safety management systems operate implementing a variety of strategies aimed at reducing the risk of fatigue-related incidents. However, the risk management, monitoring, and prevention of fatigue in the work-driving setting offers unique challenges. This chapter provides an overview of previous fatigue risk management and research and some of the unique challenges associated with the measurement of fatigue. An adapted version of Dawson and McCulloch (Sleep Med Rev 9:365–380. https://doi.org/10.1016/j.smrv.2005.03.002, 2005) Safety Error Trajectory Framework is provided along with the implications to organizational culture and work-driving safety across multiple organizational levels. This chapter concludes by suggesting a number of future directions for research and industry aiming to reduce the impact and frequency of fatigue crashes within the work environment.