In skeletal muscles, the action potential of transverse tubule membranes triggers Ca2+ release from the sarcoplasmic reticulum (SR), a process known as excitation–contraction (E-C) coupling. This release of Ca2+ is mediated by type 1 ryanodine receptor (RyR1), a Ca2+ release channel located on the SR membrane [1,2]. Mutations in RyR1 cause various muscle diseases [3,4]. To date, there are no specific treatments for most of these diseases. Recently, high-throughput screening (HTS) platforms for RyR1 modulators have been reported [5,6], and these platforms are expected to accelerate the development of specific treatments for RyR1-related muscle diseases. In this review, we will describe recent advances in HTS for RyR1 modulators and discuss future perspectives.