Calcium, as the most abundant mineral in human body, is involved in many physiological and pathological processes. Here, we reviewed the key mechanisms of calcium homeostasis, including calcium sensing receptor regulation, intestinal calcium absorption, renal calcium reabsorption and bone calcium resorption. We further discussed the roles of dietary calcium and vitamin D in diseases associated with dysfunctional regulation of calcium. However, the over-dosed consumption of calcium could increase the risks for a series of diseases, such as kidney stone, myocardial infarction and stroke.