Excitation-contraction coupling in cardiac myocytes is the result of a transient rise in cytosolic calcium. Calcium influx through voltage-dependent calcium channels, opening during the action potential, is the trigger for release of calcium from the intracellular stores, the sarcoplasmic reticulum, which supplies the largest part of the calcium that activates the myofilaments and contraction. The signaling between the L-type calcium channels in the sarcolemma, LTCC, and the calcium release channels in the sarcoplasmic reticulum, the ryanodine receptors, RyR, was proposed to be a local process (Stern, 1992). This was based on theoretical grounds and supported by the microarchitecture of LTCC and RyR in the dyadic cleft between sarcolemma and sarcoplasmic reticulum, creating a structural environment for microdomains of calcium (Franzini-Armstrong et al., 1999). Modeling of fluxes through LTCC and RyR have suggested local calcium concentrations in these microdomains to be 1 to 3 orders of magnitude larger than in the global cytosolic compartment, where [Ca2+]i can be estimated with fluorescent dyes (e.g. (Soeller & Cannell, 1997) (Shannon et al., 2004)). Because of the restricted size of the dyadic cleft and because of the limitations of the currently available calcium indicators, direct measurements and confirmation of these predictions are not yet available. Nevertheless there is indirect evidence for these high microdomain calcium transients, as well as some more quantitative estimates, using ‘natural’ reporters, i.e. calcium-sensitive ion currents that are located within the same dyadic cleft, the LTCC and the Na/Ca exchanger, NCX (e.g. (Acsai et al., 2011;Trafford et al., 1995)). Na homeostasis, regulated by voltage-dependent Na channels and the Na/K pump, through NCX, modulates and contributes to the microdomain [Ca2+] (Shattock et al., 2015) though the quantitative aspects are still under debate, awaiting more direct measurements. RyRs are not always within the dyad and in cells where the sarcolemma has fewer invaginations in the form of T-tubules, many RyR are not facing the sarcolemma, such as in atrial cells or in ventricular myocytes of larger mammals. These have been called orphaned (Sham et al., 1995) or non-coupled RyR (Biesmans et al., 2011) and lead to marked loss of synchrony in the global calcium signal for excitation-contraction coupling (Heinzel et al., 2011;Heinzel et al., 2002). Loss of T-tubules occurs in disease with consequences for alterations in microdomain signaling near RyRs (Dries et al., 2013). The calcium microdomain near RyRs is further populated with signaling molecules such as CaMKII and NADPH-oxidases. Recent advances in high-resolution microscopy are showing more details on the organization of RyR and associated signaling partners, as well as in the T-tubule structure and dyadic cleft. Ongoing studies of the structure-function relation in these calcium microdomain reveal changes with disease that impact on cardiac contractile function as well as arrhythmogenesis.