Ca2+ and Mg2+ are of great physiological importance in their function in neural excitability, muscle contraction, blood coagulation, bone formation, hormone secretion and cell adhesion. The human body is equipped with an efficient negative feedback system counteracting variations of the Ca2+ and Mg2+ balance. These divalents are maintained within a narrow range by the small intestine and kidney which both increase their fractional (re)absorption under conditions of deprivation. Rapid progress has recently been made in identification and characterization of the Ca2+ and Mg2+ transport proteins contributing to the delicate balance of divalent cations. Expression cloning approaches in combination with knockout mice models and genetic studies in families with a disturbed Mg2+ balance revealed novel gatekeeper proteins that belong to the super family of the transient receptor potential (TRP) channels. These epithelial Ca2+ (TRPV5 and TRPV6) and Mg2+ channels (TRPM6 and TRPM7) form prime targets for hormonal control of the active Ca2+ and Mg2+ flux from the urine space or intestinal lumen to the blood compartment. The characteristics of the newly identified transporters will be discussed and in particular the distinctive molecular regulation of these new epithelial Ca2+ and Mg2+ channels in (patho)physiological situations will be highlighted.