Important aspects of the excitation-contraction (EC) coupling process in skeletal muscle have been revealed using mechanically-skinned fibers in which the transverse-tubular system can be depolarized by ion substitution or electrical stimulation, activating the voltage-sensors which in turn open the Ca²⁺ release channels in the adjacent sarcoplasmic reticulum (SR). Twitch and tetanic force responses elicited in skinned fibers closely resemble those in intact fibers, showing that the coupling mechanism is entirely functional. It was found that ATP has to be bound to the Ca²⁺ release channels for them to be activated by the voltage-sensors and that the coupling mechanism likely involves the voltage-sensors removing the inhibitory effects of cytoplasmic Mg²⁺ on the release channels; such findings are relevant to the basis of muscle fatigue and to certain diseases such as malignant hyperthermia (MH). EC coupling is evidently not mediated by upmodulation of Ca²⁺-induced Ca²⁺ release (CICR) or by an oxidation or phosphorylation reaction. The Ca²⁺ load in the SR of skinned fibers can be set at the endogenous level or otherwise. The normal coupling mechanism functions well in mammalian fast-twitch fibers even when the SR is only partially loaded, whereas CICR is highly dependent on SR luminal Ca²⁺ and caffeine is poorly effective at inducing release at the endogenous SR Ca²⁺ load level.