Ca2+ and Mg2+ are essential ions in a wide variety of cellular processes and form a major constituent of bone. It is, therefore, essential that the balance of these ions is strictly maintained. In the last decade, major breakthrough discoveries have vastly expanded our knowledge of the mechanisms underlying epithelial Ca2+ and Mg2+ transport. The genetic defects underlying various disorders with altered Ca2+ and/or Mg2+ handling have been determined. Recently, this yielded the molecular identification of TRPM6 as the gatekeeper of epithelial Mg2+ transport. Furthermore, expression cloning strategies have elucidated two novel members of the transient receptor potential family, TRPV5 and TRPV6, as pivotal ion channels determining transcellular Ca2+ transport. These two channels are regulated by a variety of factors, some historically strongly linked to Ca2+ homeostasis, others identified in a more serendipitous manner. Herein we review the processes of epithelial Ca2+ and Mg2+ transport, the molecular mechanisms involved, and the various forms of regulation.