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1. The effect of repetitive stimulation at low frequencies (0.2–5/sec) upon isometric twitch tension was analysed in isolated muscle fibres of the frog. 2. The number of twitches until tension decreased to 10–20% of the original value (fatigue effect) was 5000–10000 in unpoisoned fibres at 20° C, 400–800 in CN-poisoned fibres at 10° C, 1800–2500 in CN-poisoned fibres at 20° C and 100–200 in CN and IAA-poisoned fibres at 1° C. 3. In fatigued fibres the overshoot of the action potential was often only a few millivolts lower than in normal fibres, the spike duration was longer, and the after-potential was increased. 4. In completely exhausted fibres, which developed no tension when they were activated, the effective memrane resistance was extremely low, the resting potential was high, and early and late after-potentials were absent. Since an exchange of external Cl by SO4 caused no depolarization, it is suggested that the decrease in resistance is due to an increase in potassium conductance. 5. A reduction of the external sodium concentration from 115 to 46 mM abolished the overshoot of the action potential, while twitch tension remained unaltered. 6. In fatigued fibres normal twitch height could be restored by the addition of caffeine, and maximal contracture tension could be obtained after a complete depolarization in a potassium sulphate solution which contained caffeine. 7. From the results quoted under 3, 5, and 6 it is concluded that neither an alteration in the action potential nor an exhaustion of energy reserves or a failure in the contractile mechanism can be regarded as the cause of fatigue. 8. In fatigued fibres the S-shaped curve which relates peak tension to membrane potential (threshold curve) was shifted by about 20 mV to more positive potentials. In addition maximal contractile strength was frequently no longer attained, even after complete depolarization. 9. The rate by which the contractility of depolarized fibres can be reactivated after a sudden repolarization, and probably also the steady relation between the state of the contractile system and membrane potential, were equal in normal and fatigued fibres. 10. Fibres recovered from fatigue within one to three hours. 11. From the results quoted under 8 and 9 it is tentatively suggested that a decline of the concentration of an “activator of contraction”—localized in some part of the tubular system—is the cause of the observed deficiency in excitation—contraction coupling.