The Na+/Ca2+ exchanger (NCX) is a key regulator of intracellular Ca2+ in cardiac myocytes, predominantly contributing to Ca2+ removal during the diastolic relaxation process but also modulating excitation-contraction coupling. NCX is preferentially located in the T-tubules and can be close to or within the dyad, where L-type Ca2+ channels face ryanodine receptors (RyRs), the Ca2+ release channels of the sarcoplasmic reticulum. However, especially in larger animals, not all RyRs are in dyads or adjacent to T-tubules, and a substantial fraction of Ca2+ release from the sarcoplasmic reticulum thus occurs at distance from NCX. This chapter deals with the functional consequences of NCX location and how NCX can modulate diastolic and systolic Ca2+ events. The loss of T-tubules and the effects on RyR function and NCX modulation are explored, as well as quantitative measurement of local Ca2+ gradients at the level of the dyadic space.