Fatigue is defined by means of subjective and neurophysiological deficits that vary as a function of time and workload. Cognitive load and task difficulty mediate fatigue. Performance deficits normally demonstrate evidence of fatigue and awareness of mental effort, although overt deficits may not be a consequence of fatigue, as increased efforts normally compensate the decline of mental resources. Subjective mental fatigue leads to increased mental effort, impaired learning and stress. Neurophysiological mechanisms affecting mental fatigue include homeostatic and circadian components of fatigue. One example is the dopamine system. Mental fatigue provokes significant changes in the brain, altering the glutamate network, particularly in challenging situations, including chronic pain and neurodegenerative disease. Coping with fatigue often requires pharmaceutical measures to maintain, or even restore, operative cognitive functions. We review fatigue and tiredness management strategies, the use of hypnotic and other drugs, short and long-term efficacy of drugs and recommendations.