Healthy cells maintain genome integrity by activating a conserved DNA damage response (DDR) pathway that halts the progression of the cell cycle and activates DNA repair. Molecular disorders preventing DDR functioning properly often predispose to cancer. Therefore DDR acts as a tumor suppressor barrier. DDR often leads to not only cell cycle arrest and DNA repair, but also induces cellular senescence and apoptosis. Ultimately, “autophagy” as a self-degradation and recycling program of cellular components can be induced by DDR. In healthy cells and the initial stage of cancer, autophagy appears to have a tumor suppressor function by eliminating damaged organelles, and protein aggregates to promote genomic instability. However, in advanced tumors, autophagy s activated, particularly as a result of hypoxia and metabolic stress, to promote tumor survival under these conditions. Autophagy can also be induced by DNA damaging chemotherapy agents in tumor cells, which mostly results in resistance to conventional cancer therapies. In addition, activation of certain oncogenes in advanced tumors may promote autophagy activation and guarantee the persistence of tumors. Thus, currently development of inhibitors targeting autophagy with potential clinical use is increasing rapidly. In this review, the DDR and autophagy signaling mechanisms, as well as the interconnecting pathways of both are highlighted. Moreover, the biological consequences of the companion of these two important cellular responses in cancer are discussed.