Compelling recent experimental results make clear that sub-cellular structures are altered in ventricular myocytes during the development of heart failure, in both human samples and diverse experimental models. These alterations can include, but are not limited to, changes in the clusters of sarcoplasmic reticulum (SR) Ca(2+)-release channels, ryanodine receptors, and changes in the average distance between the cell membrane and ryanodine receptor clusters. In this review, we discuss the potential consequences of these structural alterations on the triggering of SR Ca(2+) release during excitation-contraction coupling. In particular, we describe how mathematical models of local SR Ca(2+) release can be used to predict functional changes resulting from diverse modifications that occur in disease states. We review recent studies that have used simulations to understand the consequences of sub-cellular structural changes, and we discuss modifications that will allow for future modelling studies to address unresolved questions. We conclude with a discussion of improvements in both experimental and mathematical modelling techniques that will be required to provide a stronger quantitative understanding of the functional consequences of changes in sub-cellular structure in heart disease.