Cux (Cut homeobox) genes are present in all metazoans. Early reports described many phenotypes caused by cut mutations in Drosophila melanogaster. In vertebrates, CUX1 was originally characterized as the CCAAT-displacement protein (CDP). Another line of investigation revealed the presence of CUX1 within a multi-protein complex called the histone nuclear factor D (HiNF-D). Recent studies led to the identification of several CUX1 isoforms with distinct DNA binding and transcriptional properties. While the CCAAT-displacement activity was implicated in the transcriptional repression of several genes, some CUX1 isoforms were found to participate in the transcriptional activation of some genes. The expression and activity of CUX1 was shown to be regulated through the cell cycle and to be a target of TGF-beta signaling. Mechanisms of regulation include alternative transcription initiation, proteolytic processing, phosphorylation and acetylation. Cell-based assays have established a role for CUX1 in the control of cell cycle progression, cell motility and invasion. In the mouse, gene inactivation as well as over-expression in transgenic mice has revealed phenotypes in multiple organs and cell types. While some phenotypes could be explained by the presumed functions of CUX1 in the affected cells, other phenotypes invoked non-cell-autonomous effects that suggest regulatory functions with an impact on cell–cell interactions. The implication of CUX1 in cancer was suggested first from its over-expression in primary tumors and cancer cell lines and was later confirmed in mouse models.