CTCF is an evolutionary conserved and ubiquitously expressed protein that binds thousands of sites in the human genome. Ectopic expression of CTCF in various normal and tumoral human cell lines inhibits cell division and clonogenicity, with the consequence to consider CTCF a potential tumor‐suppressor factor. In this review article, we focused on the molecular mechanisms engaged by CTCF to modulate the expression of several key‐regulators of differentiation, cellular senescence, cell cycle control and progression, whose expression is frequently altered in tumors. Moreover, we discussed common features of CTCF at each tumor‐related DNA‐binding sequence, such as protein‐partners, post‐translational modifications, and distinctive epigenetic marks establishment. The investigation of the molecular mechanisms engaged by CTCF to modulate tumor‐related genes emphasizes the cell‐type dependency of its tumor suppressor role. Indeed, the ability of CTCF to bind their promoters strictly depends by cell‐type features as DNA methylation, BORIS‐binding and post‐translational modifications as PARYlation. J. Cell. Physiol. 227: 479–492, 2012. © 2011 Wiley Periodicals, Inc.