In skeletal muscle, Mg 2+ exerts a dual inhibitory effect on RyR1, by competing with Ca 2+ at the activation site and binding to a low affinity Ca 2+/Mg 2+ inhibitory site. Pharmacological activators of RyR1 must overcome the inhibitory action of Mg 2+ before Ca 2+ efflux can occur. In normal muscle, where the free [Mg 2+] i is ∼1 mM, even prolonged exposure to millimolar levels of volatile anesthetics does not initiate SR Ca 2+ release. However, when the cytosolic [Mg 2+] is reduced below the physiological range, low levels of volatile anesthetic within the clinically relevant range (⩽1 mM) can initiate SR Ca 2+ release, in the form of a propagating Ca 2+ wave. In human muscle fibers from malignant hyperthermia susceptible patients, such Ca 2+ waves occur when 1 mM halothane is applied at physiological [Mg 2+] i. There is increasing evidence to suggest that defective Mg 2+ regulation of RyR1 confers susceptibility to malignant hyperthermia. At the molecular level, interactions between critical RyR1 subdomains may explain the clustering of RyR1 mutations and associated effects on Mg 2+ regulation.