The incidence of primary vesicoureteral reflux is about 1% to 2% of the general population and is as high as 50% in siblings as well as offspring of affected patients, suggesting autosomal dominant inheritance. The current diagnosis of vesicoureteral reflux involves voiding cystourethrograms, which are invasive and costly. Consequently, vesicoureteral reflux screening in siblings and offspring is not routinely practiced, because of the known high risk. Early detection of vesicoureteral reflux will be valuable for prevention of reflux nephropathy, because the incidence of reflux nephropathy can be reduced effectively by antibiotic prophylaxis. Furthermore, the presence of reflux nephropathy can only be accurately assessed currently by dimercapto-succinic acid nuclear scans, which are costly, time and labor intensive, and often require conscious sedation by a pediatric anesthesiology team. As a result, the clinical assessment of reflux nephropathy is also not routinely practiced. There is a pressing need to develop less invasive and less costly tests for the early diagnosis of primary vesicoureteric reflux and reflux nephropathy. Recent molecular and genetic studies have greatly increased our understanding of vesicoureteral reflux and provide a promise of novel non-invasive tests. Targeted disruption of angiotensin type II receptor and uroplakin III genes result in the phenotype of primary vesicoureteral reflux. There are characteristic patterns of message and protein changes in the knockout animals, providing the basis for detection of genetic mutations leading to vesicoureteral reflux in humans by studying differential gene expression by functional genomics methodology. The urothelium is also known to secrete proteins into the urine. Preliminary studies showed unique fingerprints in urinary protein patterns in children with primary VUR, providing the basis for developing novel noninvasive molecular diagnostic tests of vesicoureteral reflux by proteomics methodology.