The kidney plays a vital role in the Ca2+ homeostasis by determining the excretion of Ca2+ from the body. The fine-tuning of Ca2+ excretion takes place in the distal convoluted and connecting tubule, where Ca2+ is actively reabsorbed via the transcellular pathway. A major breakthrough in completing the molecular details of this pathway was the identification of the epithelial Ca2+ channel TRPV5. Functional analysis indicated that this Ca2+ channel constitutes the rate-limiting step in transcellular Ca2+ transport in the kidney. TRPV5 is the prime target for hormonal control of active Ca2+ flux from the urine space to the blood compartment. Defective TRPV5 function could ultimately impair the Ca2+ conserving capacity of the body and could, therefore, contribute to hypercalciuria and age-related bone disorders. Ablation of the TRPV5 gene in mice seriously disturbs renal Ca2+ handling resulting in compensatory intestinal hyperabsorption and bone abnormalities. Recent developments of new TRPV5-associated proteins including calbindin and rab11a and extracellular channel regulation by klotho and tissue kallikrein as well as the identification of novel hormones with calciotropic activity has provided new insights into the molecular mechanisms underlying the regulation of the epithelial Ca2+ channel. This seminar will present the molecular regulation of TRPV5 and highlights the functional consequences for the maintenance of the body Ca2+ balance.