The p53-related genes p63 and p73 exhibit significant structural homology to p53; however, they do not function as classical tumor suppressors and are rarely mutated in human cancers. Both p63 and p73 exhibit tissue-specific roles in normal development and a complex contribution to tumorigenesis that is due to their expression as multiple protein isoforms. The predominant p63/p73 isoforms expressed both in normal development and in many tumors lack the conserved transactivation (TA) domain; these isoforms instead exhibit a truncated N-terminus (ΔN) and function at least in part as transcriptional repressors. p63 and p73 isoforms are regulated through both transcriptional and post-translational mechanisms, and they in turn regulate diverse cellular functions including proliferation, survival and differentiation. The net effect of p63/p73 expression in a given context depends on the ratio of TA/ΔN isoforms expressed, on physical interaction between p63 and p73 isoforms, and on functional interactions with p53 at the promoters of specific downstream target genes. These multifaceted interactions occur in diverse ways in tumor-specific contexts, demonstrating a functional ‘p53 family network’in human tumorigenesis. Understanding the regulation and mechanistic contributions of p63 and p73 in human cancers may ultimately provide new therapeutic opportunities for a variety of these diseases.