This chapter describes challenges faced in fatigue research and in fatigue evaluation for various purposes including crash statistics and enforcement and for selection of appropriate countermeasures. The challenges are related to both the causes and the consequences of fatigue. Differences between sleep-related and task-related fatigue are discussed in relation to countermeasures for fatigue. The chapter also describes how individual characteristics including age, chronotype, and personality influence the development of fatigue and add to the complexity of choosing appropriate fatigue countermeasures. Difficulties in measuring and providing proof that an individual is fatigued are discussed in relation to law enforcement.