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The p53 protein family consists of three transcription factors: p53, p63, and p73. These proteins share significant structural and functional similarities and each has unique biological functions as well. Although the role of p53 in cellular stress is extensively studied, many questions remain about p63 and p73. In this review we summarize current data on functional interactions within the p53 family, their regulation and roles in response to genotoxic stress. We also discuss the significance of p73 and p63 for cancer therapy and outline novel approaches in development of therapeutic drugs that specifically target the p53 family.