The endoplasmic reticulum (ER) is a morphologically and functionally diverse organelle capable of integrating multiple extracellular and internal signals and generating adaptive cellular responses. It plays fundamental roles in protein synthesis and folding and in cellular responses to metabolic and proteotoxic stress. In addition, the ER stores and releases Ca(2+) in sophisticated scenarios that regulate a range of processes in excitable cells throughout the body, including muscle contraction and relaxation, endocrine regulation of metabolism, learning and memory, and cell death. One or more Ca(2+) ATPases and two types of ER membrane Ca(2+) channels (inositol trisphosphate and ryanodine receptors) are the major proteins involved in ER Ca(2+) uptake and release, respectively. There are also direct and indirect interactions of ER Ca(2+) stores with plasma membrane and mitochondrial Ca(2+)-regulating systems. Pharmacological agents that selectively modify ER Ca(2+) release or uptake have enabled studies that revealed many different physiological roles for ER Ca(2+) signaling. Several inherited diseases are caused by mutations in ER Ca(2+)-regulating proteins, and perturbed ER Ca(2+) homeostasis is implicated in a range of acquired disorders. Preclinical investigations suggest a therapeutic potential for use of agents that target ER Ca(2+) handling systems of excitable cells in disorders ranging from cardiac arrhythmias and skeletal muscle myopathies to Alzheimer disease.