One of the basic principles that nature uses in evolution is to recycle successful concepts and create new functions by modifying existing units. This conservatism in evolution has resulted in an astonishingly high sequence identity of genes, even between evolutionarily distant species such as the nematode Caenorhabditis elegans and Homo sapiens. The recycling of successful concepts in conjunction with gene duplication events has also led to the existence of highly homologous proteins within the genome of many species. Often, these homologous proteins show similar, yet distinct functions that, in combination with their individual tissue distribution, define their specific physiological role. One prominent example is the p53 protein family, which consists of p53, p63, and p73. Recent advances in understanding the specific biological functions of these members have shed some light onto the evolution of this crucial protein family, from a germ line-specific quality-control factor to a somatic tumor suppressor. Furthermore, structures of the oligomerization domains of the mammalian paralogs, p53 and p73, and invertebrate orthologs, CEP-1 and DMP53, have delineated evolutionary changes and revealed that the oligomerization domain of p53 lacks additional stabilizing structural elements present in all other p53 family members. This suggests that p53 is the most recent evolutionary member of this protein family and predicts a mechanism for p53 activation.