The factors initiating the common etiologies of chronic renal failure remain elusive. This article reviews the evidence in support of a generalized genetic susceptibility to human end-stage renal disease, including kidney failure attributed to the systemic diseases of hypertension, diabetes mellitus, and glomerulonephritis. Molecular genetic techniques are powerful tools, assisting in the detection of the initiating factors in many complex diseases. In kidney disease, genetic methodologies complement the available anatomic, epidemiologic, and physiologic analyses. This article provides strategies to allow for the detection of human renal failure susceptibility genes. The identification of human renal failure genes would provide useful markers for disease susceptibility and speed the development of novel therapeutic strategies.