The RYR1 gene (19q 13.2) encodes the largest ion channel in humans, the type 1 ryanodine receptor which is localized to the skeletal muscle sarcoplasmic reticulum (SR) membrane. This 2.2 megadalton homotetrameric structure is responsible for gating Ca²⁺ within the sarcoplasmic reticulum and tightly regulating Ca²⁺ release into the muscle cell cytosol upon depolarization of the transverse tubule membrane. Over 800 RYR1 variations have been reported with a majority being classified as variants of uncertain significance (VUS). Pathogenic RYR1 variations are responsible for a diagnostically challenging and diverse spectrum of rare neuromuscular disorders that currently have no approved treatment. The most frequently encountered clinical phenotypes include congenital myopathies with varying degrees of severity, malignant hyperthermia (MH), and rhabdomyolysis-myalgia syndrome. MH is a potentially fatal hypermetabolic condition that manifests in a fulminant manner following exposure to certain volatile anesthetics and depolarizing neuromuscular blocking agents. Awake “MH-like” episodes have also been reported with triggers including environmental heat exposure, physical exertion, and febrile illness. This collection focuses on recent advances in diagnostic techniques, variant characterization, and high-throughput screening technologies that have potential to shorten the diagnostic odyssey for affected individuals and yield candidate therapeutics for clinical trials.