Cytolethal distending toxins (CDTs) are unique among bacterial protein toxins in their ability to cause DNA damage, due to their functional similarity to the mammalian deoxyribonuclease I (DNase I). The cellular response to CDT intoxication is characterised by activation of DNA damage-induced checkpoint responses, and the final outcome is cell type dependent. Cells of epithelial origin and normal keratinocytes are arrested in the G2 phase of the cell cycle, normal fibroblasts are also arrested in G1, while B cells die of apoptosis. CDTs are encoded by three linked genes (cdtA, cdtB and cdtC), and CdtB is the toxin subunit which possesses the DNase I-like activity. All the three genes have to be present in the bacterium in order to produce an active cytotoxin, however cytotoxic Haemophilus ducreyi CDT, purified from a CdtABC recombinant E. coli strain, contains the CdtB and CdtC subunits, suggesting that they constitute the holotoxin and that CdtC may be required for CdtB internalization. The role of the CdtA subunit is currently unknown, but it might modify and therefore activate CdtC. This review will focus on the cellular responses induced by CDTs in mammalian cells.