In the last ten years, studies of energetic metabolism in different tumors clearly indicate that the definition of Warburg effect, the main metabolic feature of cancer cells, ought to be revisited considering the metabolic plasticity of cancer cells. In fact, recent findings show that the shift from glycolysis to re-established oxidative metabolism is required for certain steps of tumor progression, suggesting that mitochondrial function and, in particular, respiratory complex I are crucial for metabolic and hypoxic adaptation. Based on these evidences, complex I can be considered a lethality target for potential anti-cancer strategies. In conclusion, in this mini review we summarize and discuss why it is not paradoxical to develop pharmacological and genome editing approaches to target complex I as novel adjuvant therapies for cancer treatment.