The normal heartbeat is conditioned by transient increases in the intracellular free Ca2+ concentration. Ca2+ influx in cardiomyocytes is regulated by the activity of the heteromeric L-type voltage-activated CaV1.2 channel. A complex network of interactions between the different proteins forming the ion channel determines the total Ca2+ influx. Alterations in the biophysical and biochemical properties or in the biogenesis in any of these proteins can lead to serious disturbances in the cardiac rhythm. We have investigated the multi-subunit nature of the channel complex by homology with the three-dimensional structure of the closely related CaV1.1 channel. The architectural map identifies precise interaction loci between the different subunits and paves the way for elucidating the mechanistic basis for the regulation of Ca2+ balance in cardiac myocytes under physiological and pathological conditions.