Recent studies have provided valuable insight into the key mechanisms contributing to the spatiotemporal regulation of intracellular Ca release and Ca signaling in the heart. In this research highlight, we focus on the latest findings published in Biophysical Journal examining the structural organization of Ca handling proteins and assessing the functional aspects of intracellular Ca regulation in health and the detrimental consequences of Ca dysregulation in disease. These important studies pave the way for future mechanistic investigations and multiscale understanding of Ca signaling in the heart.