Fatigue has been a common symptom of warfighters who were participated in the early morning hours, late night hours, and sustained operations. Continuous operations may disrupt circadian rhythm, resulting in impaired combat capability. It is important to enhance alertness and sleep quality of warfighters for maintaining combat capability. A number of anti-fatigue strategies are available including medications. Here in, the pharmacological countermeasures of combat fatigue have reviewed, and the direction of research in the pharmacological countermeasures against combat fatigue are proposed.