The L-type Ca²⁺ channels mediate depolarization-induced influx of Ca²⁺ into a wide variety of cells and thus play a central role in triggering cardiac and smooth muscle contraction. Because of this role, clinically important classes of 1,4-dihydropyridine, phenylalkylamine, and benzothiazepine Ca²⁺ channel blockers were developed as powerful medicines to treat hypertension and angina pectoris. Molecular cloning studies revealed that the channel is subject to extensive structure-functional variability due to alternative splicing. In this review, we will focus on a potentially important role of genetically driven variability of Ca²⁺ channels in expression regulation and mutations, Ca²⁺-induced inactivation, and modulation of sensitivity to Ca²⁺ channel blockers with the perspective for new pharmacological targets.