Contraction of the heart is reliant on the shortening of individual cardiomyocytes, which is triggered by Ca2+ release from the sarcoplasmic reticulum (SR). This Ca2+ release process is initiated at sub-cellular structures called dyads, where L-type Ca2+ channels within t-tubules face Ryanodine Receptors (RyRs) in the SR. Despite the fundamental role of dyads in triggering the heartbeat, their precise functional arrangement remains unclear. In the present work, emerging techniques for 3D super-resolution imaging1 and electron microscopy have been employed to reveal the nanoscale arrangement of key dyadic proteins and membranes. This work has shown that dyadic structure and function are highly malleable. Indeed, during development, dyads are formed gradually, with progressive assembly of both t-tubules and SR and precise trafficking of L-type Ca2+ channels and RyRs.2 During diseases such as heart failure, dyads are broken down with a reversion to an immature phenotype, including both disorganization of t-tubules and dispersion of RyRs which reduce the efficiency of Ca2+-induced Ca2+release.2,3 What signals control this dyadic plasticity? We have observed that the physical stress placed on the myocardial wall is a key regulator of t-tubule structure. Importantly, the relationship between t-tubule density and wall stress is bell-shaped, with the healthy adult heart positioned on the rising phase of this curve. Thus, modest increases in workload result in compensatory remodeling of cardiomyocytes, as cells grow new t-tubules to augment Ca2+ cycling and contractility. However, markedly elevated wall stress, as occurs in the dilated failing heart, triggers decompensatory remodeling associated with reduced expression of the dyadic anchor junctophilin-2 and t-tubule loss.4 On the adjacent dyadic membrane, new data indicate that plasticity of RyR localization and function are regulated by phosphorylation of the channel. We have specifically observed that prolonged activation of Ca2+/calmodlulin-dependent protein kinase II (CaMKII) results in dispersion of RyR clusters, resulting in distributed channel arrangements and inefficient triggering of Ca2+ release reminiscent of heart failure. Indeed, CaMKII inhibition was observed to rescue RyR organization and function in failing cells, suggesting that hyperactivity of this kinase has complex pathological actions in this disease. Taken together, our data demonstrate that plasticity of dyadic structure/function is afforded by malleability of t-tubule and SR organization and the Ca2+-handling proteins within these membranes. Understanding the signals that regulate this plasticity presents an important therapeutic opportunity to strengthen the heartbeat in cardiac patients.