Ca2+ signals governing contraction of cardiac muscle are initiated by Ca2+ entry via L-type Ca2+ channels and are subsequently amplified severalfold by release of Ca2+ from the sarcoplasmic reticulum (SR). Coupling of the two sources for Ca2+ and amplification of the Ca2+ signal occur by virtue of the Ca2+-induced Ca2+ release mechanism (CICR). For this coupling to work, the Ca2+ signal has to traverse the very narrow (around 12 nm) diadic cleft separating the t-tubular cell membrane and the membrane of the Ca2+ store of the SR. Because of structural and functional similarities with neuronal synapses this narrow gap has also been termed a ‘Ca2+ synapse’. The small volume in the diadic cleft is partly occupied by densely packed proteins, most prominently by the large macromolecular complex of the Ca2+ release channel of the SR (aka the ryanodine receptor, RyR), visible in electron micrographs as ‘foot structures’. Obviously, the amplitude, kinetics and spatial features of the Ca2+ signals prevailing in the microdomain of this diadic cleft (also termed ‘fuzzy’ space) are critically important for cardiac excitation–contraction coupling (Lederer et al. 1990). This is relevant for the activation of the RyRs, for the inactivation of the L-type Ca2+ channels, as well as for the functional orchestration of several other Ca2+-sensitive modulatory proteins (e.g. sorcin, S100A1, calmodulin). Importantly, it is of interest to determine the Ca2+ sensitivities of the RyRs in situ and to understand the details of their gating modalities (e.g. coupling of RyR gating by CICR and/or via allosteric interactions between neighbouring RyRs). These mechanisms are suspected to become altered or impaired under various conditions related to diseases, such as SR Ca2+ overload, but also in the presence of redox modifications, phosphorylations or mutations of the RyRs. The details of their function is also relevant clinically, because of the arrhythmogenic potential of accidental SR Ca2+ release via hypersensitive RyRs. Despite the importance of the Ca2+ concentration prevailing in this ‘fuzzy space’, Ca2+ signals have so far only been recorded from the cytosol of cardiac muscle cells (and from some organelles, such as mitochondria and the SR). The main reason is that there are no methods available yet to record Ca2+ signals from within the microdomain of the fuzzy space. Probably the most accurate concepts of the Ca2+ signals in the diadic cleft have been derived from mathematical modelling of Ca2+ entry and diffusion in this space, some models taking into account the tortuosity of the free water space and the electrostatic interactions of Ca2+ with the negatively charged phospholipids on the inner leaflet of the cell membrane (e.g. Soeller & Cannell, 1997; Peskoff & Langer, 1998). These simulations predict that the changes of Ca2+ concentration in the fuzzy space have very rapid kinetics, essentially following and mirroring the channel openings and closings with sub-millisecond delays. The Ca2+ concentration is thought to exhibit huge dynamics in the fuzzy space, reaching up to several tens of micromolar, almost two orders of magnitude larger than the signals recorded from the cytosol. In an elegant paper published in a recent issue of The Journal of Physiology, the authors have combined a mathematical modelling approach with electrophysiological recordings of currents generated by proteins preferentially located in the fuzzy space (Acsai et al. 2011). They used two different strongly Ca2+-dependent currents as biological ‘reporter signals’: (1) the Ca2+-dependent inactivation of the L-type Ca2+ current (CaV1.2) and (2) the activity of the Na+–Ca2+ exchanger generating the membrane current INCX. Using the patch-clamp technique in the whole-cell configuration and a model-based subcomponent analysis of the reporter currents the authors were able to derive estimates of the local Ca2+ concentration in the fuzzy space. Despite this rather indirect approach the two reporter currents yielded quite similar results consistently indicating Ca2+ concentrations of around 10–15 μm in the diadic cleft during SR Ca2+ release. In terms of our quantitative knowledge about cardiac microdomain Ca2+ signalling in the diadic cleft, these numbers probably represent the ‘state-of-the art’. However, a burning question remains. Will we ever be able to record Ca2+ signals directly from the fuzzy space? This is an extremely challenging task because of the small volumes and the extreme Ca2+ signal kinetics and dynamics involved, as mentioned above. The problem of a small volume could be elegantly solved by specifically targeting a genetically engineered Ca2+ probe to the diadic cleft. However, presently available genetic Ca2+ indicators are notoriously slow and unable to reliably follow the sub-millisecond Ca2+ signals expected in this space. Conventional synthetic fluorescent indicators with low Ca2+ affinity and rapid kinetics are already available, but they distribute more or less homogeneously within the entire cytosol and there is no way to specifically pick up signals emanating from the tiny diadic volume (not even with lipid-conjugated probes). Nevertheless, a recently initiated development may offer a possible solution to this problem. This is an attempt to combine the advantages of both worlds: the precise positioning of genetic probes and the fast kinetics of synthetic chemical Ca2+ indicators. This technique involves the engineering of a protein targeting the specific site (i.e. the diadic cleft) and chemically conjugating this protein with a modified conventional fluorescent Ca2+ indicator. In one recent application of this procedure, Indo-1 has been linked to a protein using the SNAP-tag fusion protein technology. This construct was successfully used to record Ca2+ in the nuclei of muscle cells (Bannwarth et al. 2009). Further developments of this technology will hopefully allow the recording of ‘fuzzy space’ Ca2+ signals in the not so distant future.