Autosomal dominant polycystic kidney disease (ADPKD) is characterized by age-dependent growth of kidney cysts with end-stage renal disease developing in approximately 50% of affected individuals. Living donors from ADPKD families are at risk for developing ADPKD and may be excluded from renal donation if the diagnosis cannot be conclusively ruled out. Radiographic imaging may be adequate to screen for kidney cysts in most at-risk donors but may fail to identify affected individuals younger than 40 years or older individuals from families with mild disease. In this article, we report a strategy that incorporates genetic testing in the evaluation of live kidney donors at risk for ADPKD whose disease status cannot be established with certainty on the basis of imaging studies alone. We show that DNA diagnostics can be used to enhance safe donation for certain living donor candidates at risk for ADPKD.