Malignant hyperthermia (MH) and exertional/environmental heat stroke (EHS) in humans present as similar life threatening crises triggered by volatile anesthetics and strenuous exercise and/or high temperature, respectively. Many families (70-80%) diagnosed with MH susceptibility (MHS), and a few with EHS, are linked to mutations in the ryanodine receptor type-1 gene (RYR1), the Ca2+ release channel of the sarcoplasmic reticulum (SR) of skeletal muscle and key protein in excitation-contraction (EC) coupling. However, mutations in the RYR1 gene are not found in all MH families, suggesting that alternative genes remain to be identified. In our laboratory we have recently characterized a novel knockout model lacking skeletal muscle calsequestrin (CASQ1), a SR Ca2+-binding protein that modulates RYR1 function, and investigated whether these mice present a MH/EHS-like phenotype. Ablation of CASQ1 results in remodelling of the EC coupling apparatus and functional changes, which in male mice causes a striking increase in the rate of spontaneous mortality and susceptibility to trigger MH-like lethal episodes in response to halothane- and heat-stress. The demonstration that ablation of CASQ1 results in MH- and EHS-like lethal episodes validates CASQ1 as a viable candidate gene for linkage analysis in MH and EHS families where mutations in RYR1 are excluded.