SUMMARY Intracellular Ca 2+ homeostasis is a prerequisite for a healthy cell life. While cells from some mammals may suffer dysregulation of intracellular Ca 2+ levels under certain deleterious and stressful conditions, including hypothermia and ischemia, cells from mammalian hibernators exhibit a remarkable ability to maintain a homeostatic intracellular Ca 2+ environment. Compared with cells from non-hibernators, hibernator cells are characterized by downregulation of the activity of Ca 2+ channels in the cell membrane, which helps to prevent excessive Ca 2+ entry. Concomitantly, sequestration of Ca 2+ by intracellular Ca 2+ stores, especially the sarcoplasmic/endoplasmic reticulum, is enhanced to keep the resting levels of intracellular Ca 2+ stable. An increase in stored Ca 2+ in heart cells during hibernation ensures that the levels of Ca 2+ messenger are sufficient for forceful cell contraction under conditions of hypothermia. Maintenance of Na + gradients, via Na + —Ca 2+ exchangers, is also important in the Ca 2+ homeostasis of hibernator cells. Understanding the adaptive mechanisms of Ca 2+ regulation in hibernating mammals may suggest new strategies to protect nonhibernator cells, including those of humans, from Ca 2+ -induced dysfunction.