Despite advances in therapy, glioblastoma (GBM) is still the most prevalent and lethal brain tumor. Thus, it is imperative to identify new and effective therapies that could improve the lifetime of these patients. It is known that tumor cells, such as glioblastomas present metabolic reprogramming, named "Warburg effect", recognized nowadays as a hallmark of cancer. This mechanism is associated with a high dependence of tumor cells on the glycolytic metabolism to sustain energy demands and macromolecule synthesis, leading to production of high amounts of lactic and carbonic acids. These metabolic products induce microenvironment acidification, due to up-regulation of several proteins, such as monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs), to maintain the glycolytic phenotype and the intracellular physiological pH. The dependence on glycolytic metabolism and acidic microenvironment on the acquired resistance to standard therapy has been a research focus in glioblastoma therapy response. In this review, we intend to highlight evidence for the importance of lactate transporters and other pH regulators in GBMs, which are frequently overexpressed in GBMs and associated with tumor aggressiveness. Moreover, we will describe how targeting these proteins could constitute new therapeutic strategies to overcome glioma resistance to therapy.