The family of ryanodine receptor (RyR) genes encodes three highly related Ca2+ release channels: RyR1, RyR2 and RyR3. Until about 10 years ago, RyRs were essentially known only for being the Ca2+ release channels of the sarcoplasmic reticulum of striated muscles, because of the high levels of expression of the RyR1 and RyR2 isoforms in skeletal and cardiac muscles, respectively. In contrast with the above picture, the RyR3 gene has been found not to be preferentially expressed in one specific tissue, but rather to be widely expressed in various cells. This wide expression pattern has been subsequently observed also for the RyR1 and RyR2 genes, which in addition to their preferential expression in striated muscles, have been found expressed also in several other cell types, although at lower levels than in striated muscles. Thus a closer look reveals that in several cells of vertebrates two or even three RyR isoforms can be co-expressed. In this chapter we will review published work on the RyR3 gene and discuss a model where co-expression of different RyR channel isoforms is interpreted as an evolutionary solution to provide, by functional interactions of distinct isoforms of Ca2+ release channels, the several types of vertebrate cells with the cell-specific Ca2+ release machinery required for generating the sophisticated intracellular Ca2+ signals needed for optimal regulation of their functions.