During the past decade a great number of genes encoding high- and low-voltage-dependent Ca²⁺ channels and their accessory subunits have been cloned. Studies of Ca²⁺ channel structure–function relationships and channel regulation using cDNA expression in heterologous expression systems have revealed intricate details of subunit interaction, regulation of channels by protein kinase A (PKA) and protein kinase C (PKC), drug binding sites, mechanisms of drug action, the ion conduction pathway and other aspects of channel function. In recent years, however, we have arrived at the brink of an entirely new strategy to study Ca²⁺ channels by overexpressing or knocking out genes encoding these channels in transgenic mice. In this article, various models of gene knockout or gene overexpression will be discussed. This new approach will reveal many secrets regarding Ca²⁺ channel regulation and the control of Ca²⁺-dependent cellular processes.