Nephrolithiasis or renal stone disease is an increasingly common problem, and its relatively high recurrence rate demands better treatment options. The majority of patients with nephrolithiasis have stones that contain calcium (Ca), which develop upon "supersaturation" of the urine with insoluble Ca salts; hence processes that influence the delivery and renal handling of Ca may influence stone formation. Idiopathic hypercalciuria is indeed frequently observed in patients with kidney stones that contain Ca. Genetic screens of nephrolithiasis determinants have identified an increasing number of gene candidates, most of which are involved in renal Ca handling. This review provides an outline of the current knowledge regarding genetics of nephrolithiasis and will mainly focus on the epithelial Ca channel transient receptor potential vanilloid 5 (TRPV5), an important player in Ca homeostasis. Being a member of the TRP family of ion channels, TRPV5 is currently part of a revolution in structural biology. Recent technological breakthroughs in the cryo-electron microscopy field, combined with improvements in biochemical sample preparation, have resulted in high-resolution 3-dimensional structural models of integral membrane proteins, including TRPV5. These models currently are being used to explore the proteins' structure-function relationship, elucidate the molecular mechanisms of channel regulation, and study the putative effects of disease variants. Combined with other multidisciplinary approaches, this approach may open an avenue toward better understanding of the pathophysiological mechanisms involved in hypercalciuria and stone formation, and ultimately it may facilitate prevention of stone recurrence through the development of effective drugs.