Voltage-gated calcium channels are key sources of calcium entry into the cytosol of many excitable tissues. A number of different types of calcium channels have been identified and shown to mediate specialized cellular functions. Because of their fundamental nature, they are important targets for therapeutic intervention in disorders such as hypertension, pain, stroke, and epilepsy. Calcium channel antagonists fall into one of the following three groups: small inorganic ions, large peptide blockers, and small organic molecules. Inorganic ions nonselectively inhibit calcium entry by physical pore occlusion and are of little therapeutic value. Calcium-channel-blocking peptides isolated from various predatory animals such as spiders and cone snails are often highly selective blockers of individual types of calcium channels, either by preventing calcium flux through the pore or by antagonizing channel activation. There are many structure-activity-relation classes of small organic molecules that interact with various sites on the calcium channel protein, with actions ranging from selective high affinity block to relatively nondiscriminatory action on multiple calcium channel isoforms. Detailed interactions with the calcium channel protein are well understood for the dihydropyridine and phenylalkylamine drug classes, whereas we are only beginning to understand the molecular actions of some of the more recently discovered calcium channel blockers. Here, we provide a comprehensive review of pharmacology of high voltage-activated calcium channels.