As previously discussed in Chap. 13 the concept of synthetic lethality is not novel and has been extensively used to dissect yeast-signalling pathways. More recently, this concept has been embraced as a more personalised approach to cancer therapy, exploiting the fact that a tumour with a defect in pathway A will show increased sensitivity to an agent-targeting pathway B. Contextual synthetic lethality refers to a situation where one of the two pathways is lost as a result of the cellular or microenvironmental context and is rendered sensitive to loss of a second pathway. The first example of contextual synthetic lethality to be described was the use of a PARP inhibitor in hypoxic tumour cells. In this chapter we will first discuss how tumour hypoxia arises and then most importantly the effect of hypoxia on the DNA repair pathways. Finally, we will review how reduced levels of homologous recombination lead to an increased sensitivity to PARP inhibitors in hypoxic tumours.