DNA repair and damage response pathways are activated as a tumour barrier at early stages during cancer development. Here, we describe a direct link between oncogenes that start cancer outgrowth and the tumour barrier. We show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double strand breaks. The replication lesions caused by oncogenes are tumour specific and indicate that an increase in DNA damage is associated with tumour development. Such DNA lesions are similar to those produced during radiation- or chemotherapy to kill tumour cells. A new concept for cancer therapy is to amplify endogenous tumour-specific DNA lesions, to specifically kill tumour cells. This can be achieved following inhibition of DNA repair. Based on this concept we report that BRCA2 defective breast cancers can be specifically targeted using inhibitors of Poly(ADP-ribose) polymerase (PARP). We propose that, in the absence of PARP, spontaneous DNA single strand breaks collapse replication forks and trigger homologous recombination repair. We further show that BRCA2 deficient cells, as a result of their recombination deficiency, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed forks are no longer repaired. Thus, PARP activity is essential in recombination deficient BRCA2 mutated cells. We exploit this requirement to specifically kill BRCA2 deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific since only the tumours (which are BRCA2-/-) in the BRCA2+/- patients are completely defective in homologous recombination repair. The use of an inhibitor of a DNA repair enzyme alone, in the absence of an exogenous DNA damaging agent, to selectively kill a tumour represents a new concept in cancer treatment.