At least five different types of voltage-gated Ca2+ channels exist in electrically excitable mammalian cells. Only one type, the family of L-type Ca2+ channels (L channels), contains high-affinity binding domains within their alpha 1-subunits for different chemical classes of drugs (Ca2+ channel antagonists; exemplified by isradipine, verapamil and diltiazem). Their stereoselective, high-affinity binding induces block of channel-mediated Ca2+ inward currents in heart and smooth muscle, resulting in antihypertensive, cardiodepressive and antiarrhythmic effects. Amino acids involved in drug binding have recently been identified using photoaffinity labelling, chimeric alpha 1-subunits and site-directed mutagenesis. Insertion of the drug-binding amino acids enabled the transfer of drug-sensitivity into Ca2+ channels that are insensitive to Ca2+ channel antagonists ('gain-of-function' approach). In this review, Jörg Striessing and colleagues summarize the present knowledge about the molecular architecture of L channel drug-binding domains and the implications for Ca2+ channel pharmacology and drug development.