Contraction of cardiomyocytes is dependent on sub-cellular structures called dyads, where invaginations of the surface membrane (t-tubules) form functional junctions with the sarcoplasmic reticulum (SR). Within each dyad, Ca2+ entry through t-tubular L-type Ca2+ channels (LTCCs) elicits Ca2+ release from closely apposed Ryanodine Receptors (RyRs) in the SR membrane. The efficiency of this process is dependent on the density and macroscale arrangement of dyads, but also on the nanoscale organization of LTCCs and RyRs within them. We presently review accumulating data demonstrating the remarkable plasticity of these structures. Dyads are known to form gradually during development, with progressive assembly of both t-tubules and junctional SR terminals, and precise trafficking of LTCCs and RyRs. While dyads can exhibit compensatory remodeling when required, dyadic degradation is believed to promote impaired contractility and arrythmogenesis in cardiac disease. Recent data indicate that this plasticity of dyadic structure/function is dependent on the regulatory proteins junctophilin-2, amphiphysin-2 (BIN1), and caveolin-3, which critically arrange dyadic membranes while stabilizing the position and activity of LTCCs and RyRs. Indeed, emerging evidence indicates that clustering of both channels enables "coupled gating", implying that nanoscale localization and function are intimately linked, and may allow fine-tuning of LTCC-RyR crosstalk. We anticipate that improved understanding of dyadic plasticity will provide greater insight into the processes of cardiac compensation and decompensation, and new opportunities to target the basic mechanisms underlying heart disease.