van der Wijst J, et al. - Researchers here present a framework of the contemporary understanding of the genetics of nephrolithiasis, with a large focus on an essential player in calcium (Ca²⁺) homeostasis, the epithelial Ca²⁺ channel transient receptor potential vanilloid 5 (TRPV5). Currently, TRPV5 is known to be a part of a revolution in structural biology as it is a member of the TRP family of ion channels. High-resolution 3-dimensional structural models of integral membrane proteins, including TRPV5, have come to existence because of the current technological discoveries in the cryo-electron microscopy field, together with enhancements in biochemical sample preparation. The fields for the current application of these models include the exploration of the proteins’ structure-function link, clarify the molecular mechanisms of channel regulation, and investigate the putative influences of disease variants. Using this approach, together with other multidisciplinary approaches, the pathophysiological mechanisms implicated in hypercalciuria and stone formation may be better understood and prevention of stone recurrence may be aided via the development of effective drugs.