Voltage-gated Ca2+ channels (Cav) are the molecular triggers of regulated insulin secretion. Cav channels are multimeric proteins, in which the pore-forming alpha1 subunit determines the most important electrophysiological and pharmacological properties. The genome contains ten different genes, CACNA1A-I and S, encoding for the Cav1.1-4, Cav2.1-3 and Cav3.1-3 proteins. Excitable cells typically express a subset of different Cav channels, for example, mouse pancreatic beta-cells express both L-type Cav1.2 and R-type Cav2.3 and possibly also P/Q-type 2.1. Intriguingly, the different Cav isoforms serve specific tasks in the beta-cell. Upon glucose stimulation, L-type Cav1.2 control rapid release of insulin granules that are readily releasable, whereas R-type Cav2.3 channels become more important during sustained stimulation when late-phase insulin secretion occurs (Jing et al. 2005). The exact mechanistic background to this temporally dissociated action of the two Cav isoforms remains enigmatic. Different alternatives will be discussed in this presentation, with emphasis on the possible role of isoform-specific redox-regulation of Cav channel activity (Reinbothe et al. 2009). However, Cav channels may also affect islet function by other actions than merely acting as acute triggers of glucose-induced insulin granule exocytosis. For example, R-type Cav2.3 channels have been suggested to be transiently expressed during development of the CNS and thereby controlling formation of white matter (Chen et al. 2000). The role of inherited disturbances in Cav channel function of insulin secretion and is discussed in the light of these reports and recent data. (1) Jing, X. et al. 2005. J Clin Invest 115, 146-154. (2) Reinbothe, T.M. et al. 2009. Mol Endocrinol 23, 893-900. (3) Chen, S. et al. 2000. J Neurocytol 29, 719–728.