Given that cells progressing through mitosis with unrepaired DNA double-strand breaks (DSBs) are very likely to die, the notion that in cancer cells DNA DBSs would be continuously generated appeared unlikely. Yet, recent experimental findings suggest that in precancerous lesions and cancers, the activation of oncogenes leads to DNA replication stress and, subsequently to the formation of DNA DSBs. In precancerous lesions, the continuous generation of DNA DSBs activates the DNA damage checkpoint, raising a p53-dependent barrier to tumorigenesis. However, the DNA DSBs also lead to genomic instability. Thus, cancer development lies in the balance between the tumor-suppressing DNA damage checkpoint and the tumor-promoting oncogene-induced genomic instability.