The pathophysiology of the various forms of urinary stone disease remains a complex topic. Epidemiologic research and the study of urine and serum chemistries have created an abundance of data to help drive the formulation of pathophysiologic theories. This article addresses the associations of urinary stone disease with hypertension, cardiovascular disease, atherosclerosis, obesity, dyslipidemia, diabetes, and other disease states. Findings regarding the impact of dietary calcium and the formation of Randall's plaques are also explored and their implications discussed. Finally, further avenues of research are explored, including genetic analyses and the use of animal models of urinary stone disease.