Genomic instability is often associated with cancer and can be indicative of a poor prognosis for some types of cancer. But, is genomic instability a consequence of tumour progression or an active process that drives tumour evolution? The answer to this question has still not been entirely resolved. Many new findings have highlighted certain DNA repair pathways and cell cycle control processes that have important consequences for genomic stability and tumour cell biology. Indeed, there are numerous efforts to manipulate the DNA damage responses to selectively induce tumour cell death through catastrophic genomic instability, and some are already showing promise. Of course, radiotherapy and other existing chemotherapeutic agents should not be overlooked as therapeutic strategies by which DNA damage induces tumour cell death and there are various efforts to improve the response to radiotherapy and to understand responses (and resistance) to current cytotoxic chemotherapeutics. This series takes a look at the progress made in this field and the questions that remain about the role of genomic instability in cancer.