Emerging evidence indicates that Ca2+ is a vital factor in modulating the pathogenesis of Alzheimer's disease (AD). In healthy neurons, Ca2+ concentration is balanced to maintain a lower level in the cytosol than in the extracellular space or certain intracellular compartments such as endoplasmic reticulum (ER) and the lysosome, whereas this homeostasis is broken in AD. On the plasma membrane, the AD hallmarks amyloid‐β (Aβ) and tau interact with ligand‐gated or voltage‐gated Ca2+‐influx channels and inhibit the Ca2+‐efflux ATPase or exchangers, leading to an elevated intracellular Ca2+ level and disrupted Ca2+ signal. In the ER, the disabled presenilin “Ca2+ leak” function and the direct implications of Aβ and presenilin mutants contribute to Ca2+‐signal disorder. The enhanced ryanodine receptor (RyR)—mediated and inositol 1,4,5‐trisphosphate receptor (IP3R)—mediated Ca2+ release from the ER aggravates cytosolic Ca2+ disorder and triggers apoptosis; the down‐regulated ER Ca2+ sensor, stromal interaction molecule (STIM), alleviates store‐operated Ca2+ entry in plasma membrane, leading to spine loss. The increased transfer of Ca2+ from ER to mitochondria through mitochondria‐associated ER membrane (MAM) causes Ca2+ overload in the mitochondrial matrix and consequently opens the cellular damage‐related channel, mitochondrial permeability transition pore (mPTP). In this review, we discuss the effects of Aβ, tau and presenilin on neuronal Ca2+ signal, focusing on the receptors and regulators in plasma membrane and ER; we briefly introduce the involvement of MAM‐mediated Ca2+ transfer and mPTP opening in AD pathogenesis.—Wang, X., Zheng, W. Ca2+ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles. FASEB J. 33, 6697–6712 (2019). http://www.fasebj.org