In this review emphasis is placed on some major mechanisms involved in inspiratory muscle fatigue. It is certain that respiratory muscle fatigue is a clinical entity, with broad implication in internal medicine. As yet its prevalence is largely unknown. There is reasonable certainty of some of the mechanisms leading to fatigue, for example the effect of loads and circulation. However, the cellular mechanisms, both chemical and electrophysiological, remain obscure. In detecting respiratory muscle fatigue various tests already represent windows from which we can see the malfunction of some mechanisms, unfortunately often not understood. The ideal test to evaluate respiratory muscle fatigue (easy to perform, sensitive, specific, and reliable) has not been developed yet. The clinical identification of respiratory muscle fatigue is still developing, and only tentative guidelines for its treatment can be proposed at this stage. Clearly, much research is required to determine prevalence, establish the diagnosis, and evaluate therapy.