Cellular Ca2+ homeostasis is maintained through the integrated and coordinated function of Ca2+ transport molecules, Ca2+ buffers and sensors. These molecules are associated with the plasma membrane and different cellular compartments, such as the cytoplasm, nucleus, mitochondria, and cellular reticular network, including the endoplasmic reticulum (ER) to control free and bound Ca2+ levels in all parts of the cell. Loss of nutrients/energy leads to the loss of cellular homeostasis and disruption of Ca2+ signaling in both the reticular network and cytoplasmic compartments. As an integral part of cellular physiology and pathology, this leads to activation of ER stress coping responses, such as the unfolded protein response (UPR), and mobilization of pathways to regain ER homeostasis. •Ca2+ homeostasis is a highly integrated process controlled by calcium buffers, sensors, channels, exchangers and pumps.•ER stress coping response results in unfolded protein response (UPR).•Disturbed Ca2+ homeostasis/chronic ER stress lead to pathological situations.