Muscular fatigue. Definition, models of study and mechanisms of central and peripheral fatigue. Mammalian skeletal muscles are capable of generating enormous forces when appropriately activated. However, repeated attempts to reproduce equivalent force or power output are invariable met with failure, as characterized by an acute and progressive impairment in performance, which may persist for several days or even weeks. This phenomenon is usually named by neuromuscular fatigue. The etiology of muscle fatigue has interested exercise scientists for more than a century, yet definitive agents remain to be identified. The causes of fatigue during exercise include factors that reside in the brain (central fatigue) and in the muscles themselves (peripheral fatigue). The main goals of this review were: (i) to define and to explain the fatigue concept, by pointing out some research areas; (ii) to differentiate the common used experimental models that deal with fatigue with particular focus on in vivo study through electromyography, revealing its potential usefulness; (iii) to briefly analyse some factors involved in central fatigue showing some evidences that relate central fatigue to variations in some brain neurotransmitters and some branched chain amino acids, (iv) to analyse and to describe the different kinds of peripheral fatigue and (v) to review the role of the depletion of some energetic substrates for ATP synthesis as well as intracellular changes in calcium, H+, lactate, phosphate and ADP concentrations in metabolic fatigue. It seems reasonable to relate, at least in part, the variations in blood glucose concentrations, branched chain amino acids and the synthesis of some neurotransmitters to central fatigue. With regard to peripheral fatigue, experimental evidences have demonstrated that the reductions in mioplasmatic calcium levels impair muscle fibre tension during intense muscle contractions. Although changes in H+, lactate, Pi, ADP or ATP concentrations influence fibre strength, they do not seem to be, per se, determinant factors in muscle fatigue.