Expression of the p53 tumor suppressor, which has many roles in human biology, is altered in almost all cancers. It is a highly regulated sequence-specific transcription factor that is activated by a variety of cellular stresses including DNA damage. Central to its transactivation function as a master transcriptional regulator of hundreds of genes are the DNA target sequences bound by p53, where the canonical consensus target has generally been considered to be composed of two decameric half-sites (RRRCWWGYYY) separated by a variable spacer. Knowledge of p53 binding and transactivation at various p53 target sequences is important to understanding the biological role of this well-known "guardian of the genome." Recently we reported that both wild-type and mutant p53 can also drive transactivation at noncanonical half-site response elements (REs), a finding that greatly expands the universe of genes and regions potentially affected by p53. Furthermore, we found that p53-mediated transcription can be dramatically increased in conjunction with estrogen receptor (ER) transcription factors acting in cis at a nearby ER target sequence. Here we address the functionality of canonical and noncanonical REs in supporting transactivation by both wild-type and cancer-associated mutant p53s as well as transcriptional synergism of p53 with ER. Our findings have important implications for cellular and tissue responses to various stresses.