The calcium ion (Ca(2+)) plays fundamental roles in orchestrating dynamic changes in the function and structure of nerve cell circuits in the brain. The endoplasmic reticulum (ER), an organelle that actively removes Ca(2+) from the cytoplasm, can release stored Ca(2+) through ER membrane receptor channels responsive either to the lipid messenger inositol trisphosphate (IP(3)) or to cytosolic Ca(2+). Emerging findings suggest that perturbed ER Ca(2+) homeostasis contributes to the dysfunction and degeneration of neurons that occurs in Alzheimer's disease (AD). Presenilin-1 (PS1) is an integral membrane protein in the ER; mutations in PS1 that cause early-onset inherited AD increase the pool of ER Ca(2+) available for release and also enhance Ca(2+) release through ER IP(3)- and ryanodine-sensitive channels. By enhancing Ca(2+) flux across the ER membrane, PS1 mutations may exaggerate Ca(2+) signaling in synaptic terminals and thereby render them vulnerable to dysfunction and degeneration in the settings of aging and amyloid accumulation in AD.