Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenomic disorder with variable penetrance. Over 400 causative mutations in the RYR1 gene (chromosome 19q13.1) have been identified, with additional rare mutations in CACNA1S (the dihydropyridine receptor). The ryanodine receptor is a massive calcium release channel in the sarcoplasmic reticulum. In MHS individuals, triggering agents cause conformational changes that lock the channel open, flooding the myoplasm with calcium. The clinician in perioperative or critical care settings must lead the MH crisis response, prescribe definitive pharmacotherapy, order appropriate monitoring and laboratory surveillance, manage multiorgan complications, coordinate genetic counseling referrals, and develop institutional MH preparedness protocols. The clinician must also recognize and differentiate MH from mimicking conditions including neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, and heat stroke.