When p73 and p63 were initially described as homologues of the tumor suppressor p53, the three family members seemed almost exchangeable, raising the question why all three were retained during evolution. It later turned out that the corresponding genes, TP63 and TP73, appear phylogenetically older than TP53, and that their targeted deletion causes severe developmental defects, in contrast to a deletion of TP53. Hence, p63 and p73 are responsible for biological effects that cannot be elicited by p53 alone. Here, we provide an overview of properties ascribed to p63 and p73 that distinguish them from p53. Differences occur at the following levels: (i) protein structure, especially with regard to the aminoterminal transactivation domains and the carboxyterminal portions unique to p63 and p73; (ii) regulation, affecting mRNA levels, posttranslational modifications and interaction with other cellular proteins; (iii) activities, resulting in the regulation of gene expression, the programming of development, and the emergence of tumors. We speculate that, during the course of evolution, p63 and p73 have first pursued a broader range of activities, whereas p53 later specialized on genome maintenance.