Chronic kidney disease (CKD) results from a wide array of processes that impair the kidney's ability to perform its major functions. As many as 20 million Americans suffer from CKD and nearly a half million from end-stage renal disease, but there are also examples of centenarians with adequate renal function. Family-based and genome-wide studies suggest that genetic differences substantially influence an individual's lifetime risk for kidney disease. One emerging theme is that evolution of genes related to host defense against pathogens may limit kidney longevity. The identification of these genetic factors will be critical for expanding our understanding of renal development and function as well as for the design of novel therapeutics for kidney disease.