Extracellular acidity and intracellular alkalinity are two of the characteristics hallmarks of malignant cells and their environment. This involves an inversion of the extracellular/intracellular pH gradient when compared with normal cells and it gives malignant cells proliferative and invasive advantages. Thus, the reversal of the pH gradient is a legitimate objective in the treatment of cancer and may be accomplished with drugs already used for other purposes and/or with specific new drugs that are currently being studied. The aim of this review is to describe a triple approach for reversing this gradient inversion using the concerted utilization of proton extrusion inhibitors, mitochondrial poisons and lysosomal poisons that should act synergistically through different mechanisms. The scheme presented here is compatible with almost all the chemotherapeutic protocols currently being used.