The word "fatigue" has several meanings: in daily life, it is often used to express tiredness or weakness, whereas a technical definition may also include impaired intellectual or motor performance, increased EMG activity for a given performance, shift of the EMG power spectrum to lower frequencies, and/or the inability of muscle to generate force. In an NHLBI workshop, fatigue was defined as a loss of capacity to develop force and/or velocity in response to a load, which is reversible by rest [1]. As a first approximation, fatigue of the respiratory muscles may be defined as an inability to continue to generate sufficient pressure to maintain alveolar ventilation. Fatigue is distinguished from weakness, a reduction in force generation that is fixed and not reversible by rest, although muscle weakness may be a predisposition to muscle fatigue. Despite the considerable amount of research that has been done over the past century, the site and mechanism of fatigue remain subjects of controversy. Theoretically, fatigue may occur at any point along the extensive chain of command involved in voluntary muscle contraction, beginning with the brain and ending with the contractile machinery (i.e. brain, spinal cord, nerve, neuromuscular junction, muscle cell membrane, transverse tubular system, calcium release, actin-myosin activation and crossbridge formation) (Fig. 1). Globally, fatigue is subdivided into two categories: failure to generate force due to reduced central motor output (central fatigue) and failure to generate force due to fatigue either at the neuromuscular junction or within the muscle machinery (peripheral fatigue). The question, first formulated in the early part of this century [2], thus arises: when the respiratory system is presented with a fatiguing load, do the respiratory controllers become too tired to drive the muscles to maintain adequate ventilation, or do the muscles themselves become unable to generate the required force, despite on adequate neural drive? Davies, Haldane and Priestly the first researchers to study respiratory muscle fatigue, affirmed the existence of both types of fatigue, central and peripheral. Recently, an increasing amount of evidence has emerged in support of the notion that roughly equal proportions of the force decline during diaphragmatic fatigue can be attributed to reduced central motor drive and peripheral muscle contractile failure, respectively [1, 3]. However, it is not yet clear whether such a depression of the central nervous system (CNS) is due to a primary central failure or to a protective adaptation of the CNS to changes in the contracting muscle, intended to prevent an undue reduction of intrinsic muscle fiber strength.