The incidence and prevalence rates of most forms of chronic kidney disease (CKD) had steadily been increasing for the past 30 years, although these rates now appear to have reached a plateau. It is clear that an individual’s likelihood of developing progressive CKD results from complex interactions between multiple genetic and environmental factors. Familial clustering of CKD and end-stage renal disease (ESRD) is observed among all the common etiologies of nephropathy. This article reviews the epidemiology of the familial clustering of kidney disease, as well as potential environmental and genetic contributors. The related impact of familial clustering of cardiovascular disease (CVD) and the impact of CVD on the current epidemic of ESRD is also discussed. It is imperative that nephrologists and primary care physicians recognize that individuals who have relatives with advanced nephropathy are themselves at high risk for subsequent kidney disease, proteinuria, and atherosclerotic cardiovascular complications. Until kidney failure genes are identified, it is reasonable to use “family history” (FH) as a surrogate marker for risk of future nephropathy. The detection of kidney disease genes holds great promise for detecting novel pathways that initiate renal fibrosis and lead to progressive loss of renal function. These pathways are likely to offer new therapies that may slow or halt development of chronic kidney failure.