p73, a member of the p53 family, has been shown to exhibit similar biochemical activities to that of p53. However, in contrast to p53, p73 is rarely mutated in human tumors and p73 mutant mice develop neurological, pheromonal, and inflammatory defects, but not spontaneous tumors. Furthermore, p73 mutant mice are deficient in the physiological control of cerebral spinal fluid. To determine what mediates these p73 activities, cDNA subtraction assay was performed to identify cellular genes that are regulated by p73. We found that aquaporin 3 (AQP3), a glycerol and water transporter, is regulated by p73. In addition, we identified a potential p53 response element in the promoter of the AQP3 gene, which is responsive to p73. This suggests that AQP3 may mediate the activity of p73 in maintaining cerebral spinal fluid dynamics.