Ca²⁺, one of the major intracellular messengers, plays essential roles in neuronal development, synaptic transmission and plasticity, as well as in the regulation of metabolic pathways. A perturbed Ca²⁺ homeostasis has been demonstrated in Alzheimer’s Disease (AD), one of the most devastating neurological disorder of the elderly. Although the majority of AD cases are sporadic, a small fraction is inherited in a dominant pattern (Familial AD, FAD). Of the three genes involved in the pathogenesis of FAD, two code for the ubiquitously expressed proteins presenilin (PS) 1 and 2. Mutations in PSs have variably been correlated to alterations of Ca²⁺ signalling and different molecular targets have been identified, suggesting a physiological role for these proteins in multiple intracellular Ca²⁺ pathways. According to the popular “Ca²⁺ overload” hypothesis for FAD pathogenesis, PS mutations increase the Ca²⁺ content of the endoplasmic reticulum (ER), thus sensitizing neurons to excitotoxicity and progressive degeneration. The latter process is closely linked to exaggerated ER Ca²⁺ release that, in turn, causes abnormal mitochondrial Ca²⁺ uptake and cell death. New evidence from different groups has however shown exceptions to this scenario: in fact, in addition to an increased, also a reduced, or even an unchanged, ER Ca²⁺ content has been described in cells over-expressing wild type or FAD mutant PSs. Altogether, these findings suggest that Ca²⁺ dysregulation in FAD is variable in nature, depending on the type of mutation and the cell model under investigation, thus appearing as a modulator rather than a causing event in AD pathogenesis.