Calcium (Ca(2+)) and magnesium (Mg(2+)) ions are involved in many vital physiological functions. In the human body, Ca(2+) and Mg(2+) homeostatic systems rely on three components: (i) tissues (re)absorbing or storing Ca(2+) and Mg(2+), mainly kidney, intestine, and bone; (ii) hormones that modulate the transport and mobilization of these minerals; and (iii) sensors controlling the transport of Ca(2+) and Mg(2+) in tissues. So far, the Ca(2+)-sensing receptor (CaSR) is the only known sensing mechanism involved in the response to systemic and local fluctuations in Ca(2+) and Mg(2+) concentrations. The tight coupling of the Ca(2+) and Mg(2+) homeostasis is frequently observed in humans and in animal models. Moreover, during the past decade, the intense research on mineral disorders, seen in the course of chronic kidney disease with secondary hyperparathyroidism, has revealed the interplay between Ca(2+) and Mg(2+) homeostasis. Altogether this evidence points to the CaSR as an interesting target to study mutual disturbances in Ca(2+) and Mg(2+) balance. Although many homeostatic processes involving CaSR in the parathyroid glands and kidneys have been elucidated, the current knowledge of the inter-regulation of divalent handling by the CaSR is still limited. Insight into the systemic and local sensing of Ca(2+) and Mg(2+) by the CaSR, as well as the identification of other receptors/sensors for these cations, will unravel the mechanism controlling their coupled regulation, and will lead to new treatment concepts for mineral disorders.