TRPV5 and TRPV6 are unique members of the TRP super family. They are highly selective for Ca 2+ ions with multiple layers of Ca 2+-dependent inactivation mechanisms, expressed at the apical membrane of Ca 2+ transporting epithelia, and robustly responsive to 1,25-dihydroxivitamin D 3. These features are well suited for their roles as Ca 2+ entry channels in the first step of transcellular Ca 2+ transport pathways, which are involved in intestinal absorption, renal reabsorption of Ca 2+, placental transfer of Ca 2+ to fetus, and many other processes. While TRPV6 is more broadly expressed in a variety of tissues such as esophagus, stomach, small intestine, colon, kidney, placenta, pancreas, prostate, uterus, salivary gland, and sweat gland, TRPV5 expression is relatively restricted to the distal convoluted tubule and connecting tubule of the kidney. There is only one TRPV6-like gene in fish and birds in comparison to both TRPV5 and TRPV6 genes in mammals, indicating TRPV5 gene was likely generated from duplication of TRPV6 gene during the evolution of mammals to meet the needs of complex renal function. TRPV5 and TRPV6 are subjected to vigorous regulations under physiological, pathological, and therapeutic conditions. The elevated TRPV6 level in malignant tumors such as prostate and breast cancers makes it a potential therapeutic target. TRPV6, and to a lesser extent TRPV5, exhibit unusually high levels of single nucleotide polymorphisms (SNPs) in African populations as compared to other populations, indicating TRPV6 gene was under selective pressure during or after humans migrated out of Africa. The SNPs of TRPV6 and TRPV5 likely contribute to the Ca 2+ conservation mechanisms in African populations. © 2011 Springer Science+Business Media B.V.