Increase in intracellular Ca(2+) concentration occurs by Ca(2+) influx through the plasma membrane and by Ca(2+) release from intracellular stores. The ER is the most important Ca(2+) store. Its stress, characterized by the impairment of Ca(2+) homeostasis and by the accumulation of misfolded proteins, can be induced by different factors. In turn, it induces defense mechanisms such as unfolded protein response, and when it is severe and prolonged, activation of the apoptotic pathway. Damage to the ER, impairment of its function, and a decreased level of its Ca(2+)-handling proteins might all play a role in physiological ageing by handicapping the ER stress response. Thus, healthy ageing is accompanied by subtle alterations of Ca(2+) homeostasis and signaling, including alterations in the ER Ca(2+) load and release. The expression and/or function of ryanodine receptors, IP3 receptors, and SERCA Ca(2+) pumps located in the ER membrane, and Ca(2+)-binding proteins within ER lumen all seem to be affected in aged cells. Data are presented on age-dependent, tissue-specific changes in ER-related Ca(2+) homeostasis in skeletal, cardiac and smooth muscles, as well as in the nervous and immune systems. Disturbances of Ca(2+) homeostasis and of signaling are potential targets for intervention in aged humans.