Calcium influx through voltage gated L-type Ca²⁺ channels has evolved as one of the most widely used transmembrane signalling mechanisms in eukaryotic organisms. Although pharmacological inhibitors of L-type Ca²⁺ channels have an important place in medical therapy, the full therapeutic potential of the 4 L-type Ca²⁺ channel subtypes has not been explored yet. To dissect the physiological relevance of the L-type Ca²⁺ channel subtype diversity, gene-targeted mouse models carrying deletions of these channels (“knockout mice”) have been generated. This review focuses on recent data from studies in mice lacking the Ca_v1.2 and Ca_v1.3 pore subunits, which have elucidated some of the roles of L-type Ca²⁺ channels as mediators of signalling between cell membrane and intracellular processes like blood pressure regulation, smooth muscle contractility, insulin secretion, cardiac development, and learning and memory.