We report the case of 2 pediatric patients with coexisting diagnoses of malignant hyperthermia susceptibility and mitochondrial disease in 2 different surgical settings. Due to the rare occurrence of each disorder, and even more so together, we reviewed evidence-based anesthetic concerns and described our perioperative management, with the goal of aiding future practitioners in safely caring for these patients. Consent was obtained for both patients, as well as IRB approval before publication.