Perturbed neuronal Ca²⁺ homeostasis is implicated in age-related cognitive impairment and Alzheimer's disease (AD). With advancing age, neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subcellular Ca²⁺ dynamics. Toxic forms of amyloid β-peptide (Aβ) can induce Ca²⁺ influx into neurons by inducing membrane-associated oxidative stress or by forming an oligomeric pore in the membrane, thereby rendering neurons vulnerable to excitotoxicity and apoptosis. AD-causing mutations in the β-amyloid precursor protein and presenilins can compromise these normal proteins in the plasma membrane and endoplasmic reticulum, respectively. Emerging knowledge of the actions of Ca²⁺ upstream and downstream of Aβ provides opportunities to develop novel preventative and therapeutic interventions for AD.