AbstractActivating Transcription Factor‐2 is a sequence‐specific DNA‐binding protein that belongs to the bZIP family of proteins and plays diverse roles in the mammalian cells. In response to stress stimuli, it activates a variety of gene targets including cyclin A, cyclin D and c‐jun, which are involved in oncogenesis in various tissue types. ATF‐2 expression has been correlated with maintenance of a cancer cell phenotype. However, other studies demonstrate an antiproliferative or apoptotic role for ATF‐2. In this review, we summarize the signaling pathways that activate ATF‐2, as well as its downstream targets. We examine the role of ATF‐2 in carcinogenesis with respect to other bZIP proteins, using data from studies in human cancer cell lines, human tumours and mouse models, and we propose a potential model for its function in carcinogenesis, as well as a theoretical basis for its utility in anticancer drug design. BioEssays 30:314–327, 2008. © 2008 Wiley Periodicals, Inc.