Cav1.2 channels in the heart mediate excitation-contraction (E-C) coupling; tune cardiac excitability; and regulate gene expression. In ventricular myocytes, CaV1.2 channels are predominantly located in t-tubules where they are in proximity to ryanodine receptors to trigger cardiac E-C coupling. A subset of ventricular CaV1.2 channels existing on the surface sarcolemma, including in caveolae, have less well-defined functions. Cardiac CaV1.2 channels are famously up-regulated by protein kinase A as a component of the 'fight-or-flight' response. The molecular details of how this kinase regulates cardiac CaV1.2 channels are controversial and under intensive study. Here, we critically review recent work addressing the putative functions of microdomain cardiac CaV1.2 channels, and their regulation by distinct kinases in health and disease.