Apoptosis or programmed cell death is a cellular mechanism used to regulate cell number and eliminate damaged or mutated cells. Many chemotherapeutic agents and ionizing radiation induce not only apoptotic signaling pathways, but also survival responses such as DNA damage responses and cell cycle arrest, which allow for DNA repair. These survival responses determine the toxicity as well as the efficacy of the cancer treatment. Two main DNA damage responses include the activation of the anti-apoptotic transcription factor NF-κB and the activation of cell cycle checkpoint kinases. Strategies of combining chemotherapeutics with (a) inhibitors of NF-κB or (b) inhibitors of checkpoint kinases, may therefore enhance the efficacy of current cancer therapies. This review will be focused on recent progress made in combining traditional chemotherapeutic drugs with small molecule inhibitors of NF-κB and the checkpoint kinases, Chk1 and Chk2.