Dysregulation of DNA damage repair and signalling to cell cycle checkpoints is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. We describe the role of Cyclin O in the regulation of DNA damage repair and in the activation of the cellular DNA damage checkpoints. Cyclin O is also a crucial regulator of the generation of multiciliated cells through modulation of the activity of the ciliogenic transcription factors FoxJ1 and Myb. It is also necessary for deuterosome-mediated centriole amplification and for apical docking of the basal bodies, the cilia-anchoring structures. Most human tumors show overexpression of Cyclin O. In vitro modification of cellular levels of Cyclin O leads to the generation of aberrant mitotic spindles due to centrosome amplification and to the appearance of stable polyploid cell clones. Our working hypothesis assumes that expression of Cyclin O in non-ciliated cells leads to deuterosome-mediated centriole amplification and consequent multipolar, aberrant mitotic spindle formation. Cyclin O expression in epithelial cells that have acquired a preneoplastic lesion as a consequence of the activation of the DNA damage response may be linked to the appearance of aneuploidy and genomic instability. Currently we are exploring the participation of Cyclin O in the transformation of preneoplasic lesions into full blown tumours.