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.