In excitable cell types, activation of cell-surface Ca(2+) channels triggers Ca(2+) release from the endplasmic or sarcoplasmic reticulum (ER/SR). This Ca(2+) signal amplification, termed Ca(2+)-induced or voltage-induced Ca(2+) release (CICR/VICR), requires the ryanodine receptor as an intracellular Ca(2+) channel, which is predominantly localized in the junctional membrane complex between the plasma membrane and the ER/SR. Junctophilin is an ER/SR membrane protein that contributes to the formation of the junctional membrane structure. Ryanodine receptor and junctophilin subtypes are derived from distinct genes and show different tissue-specific expression. Recent gene-knockout studies have defined physiological functions of both Ca(2+) release via ryanodine receptors and junctional membrane structures constituted by junctophilins in excitable cells. Moreover, several human genetic diseases are caused by mutations at the ryanodine receptor and junctophilin subtype genes.