In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63 and TP73, respectively). The usage of two alternative promoters produces protein variants either with (TA isoforms) or without (ΔN isoforms) the N-terminal transactivation domain. In general, the TA proteins exert TP53-like tumor suppressive activities through their ability to activate a common set of target genes. The ΔN proteins can act as dominant negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic specific biological activities due to the presence of alternative transactivation domains, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those, which are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks amongst the TP53 family members, their modulators as well as the transcriptional targets. This article is protected by copyright. All rights reserved.