The formation of stones in the urinary tract stems from a wide range of underlying disorders. That clinicians look for the underlying causes for nephrolithiasis is imperative to direct management. There are many advances in genetics, pathophysiology, diagnostic imaging, medical treatment, medical prevention, and surgical intervention of nephrolithiasis. Here, I provide a brief general background and focus mainly on pathophysiology and medical treatment of kidney stones. Although important advances have been made in understanding nephrolithiasis from single gene defects, the understanding of polygenetic causes of kidney stones is still largely elusive. A substantial proportion of data that resulted in new methods of treatment and prevention, which can be empirical or definitive, has focused on urinary luminal chemical composition of the precipitating solutes. Manipulation of inhibitors and epithelial factors is important and needs further investigation. Advances in the management of nephrolithiasis depend on combined efforts of clinicians and scientists to understand the pathophysiology.