Ca(2+) channel blockers such as 1,4-dihydropyridines, phenylalkylamines, diltiazem and mibefradil exert their anti-arrhythmic and anti-hypertensive action by restricting Ca(2+) entry into myocardial cells and smooth muscle cells. Binding sites for these drugs are present on the pore-forming alpha(1)-subunits of voltage-dependent Ca(2+) (Ca(v)) channels. However, striking new data show that auxillary beta-subunits also influence drug sensitivity significantly. These findings are summarized and the underlying molecular mechanisms and their pharmacological relevance are discussed.