This review attempts to give an insight into the key aspects of excitation-contraction (E-C) coupling and fatigue in skeletal muscle, in particular summarizing the results and perspectives obtained from studies with mechanically skinned muscle fibres. These skinned fibre studies have provided many novel insights, such as the role of intracellular Mg2+ and ATP in the coupling mechanism, as well as how the accumulation of metabolic products, precipitation of inorganic phosphate in the sarcoplasmic reticulum (SR) and disruption of the coupling mechanism by high intracellular [Ca2+], may contribute to different types of muscle fatigue. The recent demonstration of action potential (AP)-induced Ca2+ release in skinned fibres [G.S. Posterino et al. (2000) J Physiol 527: 131-137] showed unequivocally that the normal E-C coupling mechanism [W. Melzer et al. (1995) Biochim Biophys Acta 1241: 59-116] was retained in this preparation and indicated the considerable potential of this technique. Among other things, it has been possible to show that AP activation of the voltage-sensors in the transverse-tubular (T-) system is normally sufficient to give maximal activation of the Ca2+ release channels (ryanodine receptors) in the SR and that increasing the sensitivity of the release channels to Ca2+, such as by oxidation or other means, does not increase the amount of Ca2+ released by an AP. In contrast, when the voltage-sensors are not fully activated, modulating the responsiveness of the Ca2+ release channels does affect the amount of Ca2+ release. It is suggested that some forms of muscle fatigue are caused by inadequate activation of the Ca2+ release channels due both to (a) inactivation or dysfunction of the voltage-sensors and (b) inhibitory effects on the release channels caused by local changes in the cytoplasmic environment (in particular by low [ATP] and raised concentrations of Mg2+, ATP metabolites and other factors) and by a decrease in the pool of releasable Ca2+ within the SR.