The pharmacogenetic disorder malignant hyperthermia is an inherited myopathy, characterised by a metabolic response to volatile anesthetics in predisposed individuals. The typical symptoms of a hyper-metabolic crisis include hyperthermia, muscle rigidity, hypoxia and acidosis. Mutations in regulatory elements of the excitation-contraction coupling process in skeletal muscles, the RyR1 isoform of the ryanodine receptor Ca²⁺-release channel and the α_1S-subunit of the voltage-sensing dihydropyridine receptor, confer susceptibility to malignant hyperthermia. Recently, protein gel shift analyses with halothane-treated microsomes from normal and susceptible specimens demonstrated clustering of the Ca²⁺-ATPase at comparable halothane levels, while anesthetic-induced oligomerisation of the RyR1 complex occurred at a lower threshold concentration in the sarcoplamic reticulum from patients with malignant hyperthermia. Hence, decreased Ca²⁺-loading of the pathological sarcoplasmic reticulum appears not to be due to a modified expression of Ca²⁺-regulatory proteins, but is more likely triggered by alterations in the supramolecular structure or modified functional dynamics within Ca²⁺-handling complexes. This review discusses the role of increased RyR1 complex formation and decreased Ca²⁺-uptake in the pathophysiological development of a metabolic crisis in malignant hyperthermia.