Our study strongly suggests that ALDHi increase cancer cell death in part through the generation of DNA double strand breaks (DSB); ALDHi significantly increase the tail moments of neutral Comet assays which directly measure DSB, ALDHi increase phosphorylation of CHK1 and CHK2 which serve as a DSB checkpoint, and ALDHi synergize with inhibitors ATM and ATR which recognize both direct and replication induced DSBs. Here, ATR is linked to cancer.