The excitation-contraction-relaxation cycle of skeletal muscle fibres depends on the finely tuned interplay between the voltage-sensing dihydropyridine receptor, the junctional ryanodine receptor Ca²⁺-release channel and the sarcoplasmic reticulum Ca²⁺-ATPase. Inherited diseases of excitation-contraction coupling and muscle relaxation such as malignant hyperthermia, central core disease, hypokalemic periodic paralysis or Brody disease are caused by mutations in these Ca²⁺-regulatory elements. Over twenty different mutations in the Ca²⁺-release channel are associated with susceptibility to the pharmacogenetic disorder malignant hyperthermia. Other mutations in the ryanodine receptor trigger central core disease. Primary abnormalities in the alpha-1 subunit of the dihydropyridine receptor underlie the molecular pathogenesis of both hypokalemic periodic paralysis and certain forms of malignant hyperthermia. Some cases of the muscle relaxation disorder named Brody disease were demonstrated to be based on primary abnormalities in the Ca²⁺-ATPase. Since a variety of other sarcoplasmic reticulum proteins modulate the activity of the voltage sensor, Ca²⁺-release channel and ion-binding proteins, mutations in these Ca²⁺-regulatory muscle components might be the underlying cause for novel, not yet fully characterized, genetic muscle disorders. The cell biological analysis of knock-out mice has been helpful in evaluating the biomedical consequences of defects in ion-regulatory muscle proteins.