The release of Ca2+ from intracellular stores is a key step in a wide variety of biological functions, most notably excitation-contraction and excitation-secretion coupling as well as transcription and apoptosis. This release is mediated by two related families of calcium release channels, the ryanodine receptors RyR) and the inositol l, 4, 5-trisphosphate receptors IP3R). Both the RyRs and IP3Rs are expressed in specialized subcompartments of the smooth endoplasmic reticulum, containing micromolar to millimolar concentrations of both free and bound Ca2+. Ca2+ release through these high-conductance channels is triggered by ligand binding, either via a voltage-sensing molecule in the surface membrane or Ca2+ in the case of RyRs, or via the concerted action of IP3 and Ca2+ in the case of IP3Rs, resulting in rapid increase in cytosolic free Ca2+ content before the channels close. Given the fundamental importance of the release events, both channel subfamilies are modulated by myriad pathways through small molecules and protein-protein interactions [Fig. 1 and reviews of RyRs Coronado et al., 1994; Meissner, 1994; Sutko & Airey, 1996; Franzini-Armstrong & Protasi, 1997; Zucchi & Ronca-Testoni, 1997) and IP3Rs Mikoshiba, 1997; Yoshida & Imai, 1997; Taylor & Broad, 1998; MacKrill, 1999)]. This review focuses on the regulation of the two intracellular calcium-release channel subfamilies by calmodulin CaM), a small calcium-binding protein that is a key modulator of many steps in a wide variety of Ca2+-signaling pathways.