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A common emotional human anomaly is the manifestation of fatigue which is felt as an overall symptom in times of sickness and disease, but also during and after exercise as a specific or general symptom of exhaustion and over exertion. The main culprit of fatigue during illness is thought to be the immune/inflammatory response that occurs as the body attempts to fight off the invading virus or bacteria. Numerous models of fatigue have been developed to help us understand its mechanisms in both disease and exercise, but none so far have specifically discussed the interactions between cytokine release during exercise and its effects on afferent feedback and processing of signals in the brain that might lead to sensations and feelings of fatigue. Therefore, this article examines the literature in a range of disciplines spanning exercise, disease, immunology, and neurology, in order to develop a neuroinflammatory model for acute fatigue during exercise, similar to that which we often feel during illness.