Different types of voltage-gated Ca2+ channels exist in the plasma membrane of electrically excitable cells. By controlling depolarization-induced Ca2+ entry into cells they serve important physiological functions, such as excitation-contraction coupling, neurotransmitter and hormone secretion, and neuronal plasticity. Their function is fine-tuned by a variety of modulators, such as enzymes and G-proteins. Block of so-called L-type Ca2+ channels by drugs is exploited as a therapeutic principle to treat cardiovascular disorders, such as hypertension. More recently, block of so-called non-L-type Ca2+ channels was found to exert therapeutic effects in the treatment of severe pain and ischemic stroke. As the subunits of different Ca2+ channel types have been cloned, the modulatory sites for enzymes, G-proteins, and drugs can now be determined using molecular engineering and heterologous expression. Here we summarize recent work that has allowed us to determine the sites of action of L-type Ca2+ channel modulators. Together with previous biochemical, electrophysiological, and drug binding data these results provide exciting insight into the molecular pharmacology of this voltage-gated Ca2+ channel family.