Malignant tissues show a peculiar feature regarding pH: while normal tissues have a higher extracellular pH than intracellular pH, in cancer is exactly the opposite. This phenomenon is called the inversion of the pH gradient and is now considered a hallmark of malignancy. For some time, this inverted pH gradient was believed to be a secondary effect of cancer. Now, it is becoming clear that pH inversion is not an innocent consequence, but a key player in the etiopathogenesis of cancer. Therefore, addressing this issue as part of an integral treatment of neoplasia should be a necessary step for improving cancer patients' outcomes. However, the knowledge acquired in this regard through basic research has not reached bedside treatments. The most striking fact is that there are repurposed drugs and nutraceuticals with low or no toxicity that can modify the pH gradient inversion. However, these drugs have not even been tested in cancer treatment.