Over the past 50 yr, many drugs have been implicated as triggers of malignant hyperthermia (MH), a potentially fatal pharmacogenetic disorder of skeletal muscle calcium regulation. This review discusses the potent inhalation agents as the principal triggers and evidence that the modern agents, desflurane, sevoflurane, and isoflurane, can cause florid MH reactions in the same way as halothane but also are associated with reactions whose onset is delayed for several hours into anaesthesia. There is evidence that the triggering of MH by drugs is dose-dependent but the minimum dose that will trigger the condition is unknown. This has implications for the preparation of anaesthetic machines when used for known or suspected MH patients. While succinylcholine enhances the response of potent inhalation anaesthetics, its role as an inherent trigger of the condition is controversial. Non-depolarizing neuromuscular blocking drugs appear to protect against the development of MH and this may be by blocking excitation-coupled calcium entry-a recently described route of skeletal muscle calcium entry that may also explain the mechanism of the effect of succinylcholine in MH. Another mechanism for extracellular calcium influx, store-operated calcium entry, is activated in MH muscle and may explain how a triggered reaction is sustained. Finally, reports of drugs that have been implicated as additional triggers of MH over the past 10 yr are discussed.