p53, a transcription factor, exerts its tumor suppressor activity by regulating a diverse array of genes involved in the control of the cell cycle, apoptosis, differentiation, and DNA repair. Previously, we and others have found that p53 contains multiple separate functional domains, each of which has a unique contribution to the activity of p53 in inducing cell cycle arrest and apoptosis, probably via differential regulation of target genes. We and others have also found that the p53 family members, that is, p53, p63, and p73, are all capable of inducing cell cycle arrest and apoptosis and regulate both common and unique target genes. Here, we used Affymetrix GeneChip assay and Northern blot analysis to determine whether some known target genes are regulated by various p53 mutants, which are active in inducing cell cycle arrest, apoptosis, or both, and to identify novel target genes regulated by the p53 family. We found that various p53 functional domains control the induction of a target gene, which may be responsible for the unique activity of a given functional domain in inducing cell cycle arrest or apoptosis. In addition, we identified fourteen potential novel target genes that are differentially regulated by various p53 family members. Therefore, the regulation of a known target gene by a defined p53 mutant can be used to classify the role of the target gene in p53 tumor suppression and the identification of these fourteen potential novel target genes of the p53 family can lead to uncover the signaling pathway to which a p53 family member functions in tumor suppression (p53) and in development (p63 and p73). ©2003 Landes Bioscience.