Fatigue can be a significant problem for commercial motor vehicle (CMV) drivers. The lifestyle of a long-haul CMV driver may include long and irregular work hours, inconsistent sleep schedules, poor eating and exercise habits, and mental and physical stress, all contributors to fatigue. Shiftwork is associated with lacking, restricted, and poor-quality sleep and variations in circadian rhythms, all shown to negatively affect driving performance through impaired in judgment and coordination, longer reaction times, and cognitive impairment. Overweight and obesity may be as high as 90% in CMV drivers, and are associated with prevalent comorbidities, including obstructive sleep apnea, hypertension, and cardiovascular and metabolic disorders. As cognitive and motor processing declines with fatigue, driver performance decreases, and the risk of errors, near crashes, and crashes increases. Tools and assessments to determine and quantify the nature, severity, and impact of fatigue and sleep disorders across a variety of environments and populations have been developed and should be critically examined before being employed with CMV drivers. Strategies to mitigate fatigue in CMV operations include addressing the numerous personal, health, and work factors contributing to fatigue and sleepiness. Further research is needed across these areas to better understand implications for roadway safety.