The increase in automation of cyber-physical systems is constantly growing. Although this tendency is associated with significant benefits, particularly in terms of performance or security, many challenges still need to be overcome in order to integrate the human into the loop with the aim of creating cyber-physical-human systems. In this chapter, we will see through examples from different application domains how cognitive fatigue, a cognitive state that impairs the adaptive capacities, can emerge in a human agent within a cyber-physical system. After defining this concept and highlighting its specificities, we will present different measures used to evaluate it and present the concept of physiological computing whose goal is to detect cognitive fatigue in real time. The remainder of the chapter will present countermeasures based on the biofeedback technique or other more proactive solutions focused on system design modification. Finally, we will conclude this chapter by presenting three topics to be explored in order for the research results to be beneficial from a fundamental and applied point of view, in particular for the design of cyber-physical-human system. We will emphasize the necessity of pursuing the transfer of knowledge from the laboratory to an ecological environment and especially on the importance of improving the specificity of current measures by specifying the origin of cognitive fatigue. Finally, a literature review will be presented on the conditions for recovery from cognitive fatigue.