Following exposure to xenobiotics, cellular mechanisms will take place to prevent damages relative to i) DNA, to maintain genome integrity, ii) proteins, to maintain their activities, iii) lipids, to limit peroxidation. This system of cellular defence and resistance is energetically costly. In this commentary review, we discuss the impact of DNA damage and the DNA damage response (DDR) on energetic metabolism. Conversely, we address the question about how energetic metabolism would influence DDR. These points will be highlighted in the context of cancer, in which genome instability and aerobic glycolysis are cancer hallmarks.