Physical exercise affects the equilibrium of the internal environment. During exercise the contracting muscles generate force or power and heat. So physical exercise is in fact a form of mechanical energy. This generated energy will deplete the energy stocks within the body. During exercise, metabolites and heat are generated, which affect the steady state of the internal environment. Depending on the form of exercise, sooner or later sensations of fatigue and exhaustion will occur. The physiological role of these sensations is protection of the exercising subject from the deleterious effects of exercise. Because of these sensations the subject will adapt his or her exercise strategy. The relationship between physical exercise and fatigue has been the scope of interest of many researchers for more than a century and is very complex. The exercise intensity, exercise endurance time and type of exercise are all variables that cause different effects within the body systems, which in turn create different types of sensation within the subject's mind during the exercise. Physical exercise affects the biochemical equilibrium within the exercising muscle cells. Among others, inorganic phosphate, protons, lactate and free Mg2+ accumulate within these cells. They directly affect the mechanical machinery of the muscle cell. Furthermore, they negatively affect the different muscle cell organelles that are involved in the transmission of neuronal signals. The muscle metabolites produced and the generated heat of muscle contraction are released into the internal environment, putting stress on its steady state. The tremendous increase in muscle metabolism compared with rest conditions induces an immense increase in muscle blood supply, causing an increase in the blood circulatory system and gas exchange. Nutrients have to be supplied to the exercising muscle, emptying the energy stocks elsewhere in body. Furthermore, the contracting muscle fibres release cytokines, which in their turn create many effects in other organs, including the brain. All these different mechanisms sooner or later create sensations of fatigue and exhaustion in the mind of the exercising subject. The final effect is a reduction or complete cessation of the exercise. Many diseases speed up the depletion of the energy stocks within the body. So diseases amplify the effect of energy stock depletion that accompanies exercise. In addition, many diseases produce a change of mind-set before exercise. These changes of mind-set can create sensations of fatigue and exercise-avoiding behaviour at the onset of an exercise. One might consider these sensations during disease as a feed-forward mechanism to protect the subject from an excessive depletion of their energy stocks, to enhance the survival of the individual during disease.