p63 plays a more complex role than initially thought in cancer and development. As a p53 homolog, p63 encodes transcription factors that primarily functions through regulation of downstream gene expression. However, p63 is also involved in RNA processing and activation of beta-catenin signaling. A number of genes activated by TAp63 support the notion that p63 is involved in tight transcriptional control of epithelial differentiation, cell adhesion, and tumorigenesis via cell cycle arrest, apoptosis, and other cellualr functions. In addition, DeltaNp63 isotypes retain a rather short transactivation domain and were found to transcriptionally regulate a specific set of downstream gene targets. We found that p63 is capable of activating gene expression through binding to specific cis-elements, RE1 and RE2, with the latter being more specific for p63 than for p53. Differences in p53 family members DNA binding may help to explain key differences in their function and biology.