Tumor microenvironment may play a key role in tumor malignancy. It is hypothesized that hypoxia and acidity may contribute to the progression from benign to malignant growth. In particular, the unfavorable environment may induce the selection of tumor cells able to survive in acidic and hypoxic conditions. In fact, the common components of the cancer phenotype result from active selection, and characteristics of tumor microenvironment may create the best condition for this selection. Acidity, in particular, has been shown to have a role in resistance to chemotherapy, proliferation and metastatic behavior. In fact, a mechanism of resistance to cytotoxic drugs may be the alteration of the tumor microenvironment through changes of the pH gradient between the extracellular environment and cell cytoplasm. The extracellular pH of solid tumors is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumors. An important determinant of tumor acidity is the anaerobic metabolism that allows selection of cells able to survive in an hypoxic-anoxic environment with the generation of lactate. However, this is not the major mechanism responsible for the development of an acidic environment within solid tumors. It appears clear that a complex framework of protein-protein, protein-lipid and lipid-lipid interactions underlay the pH homeostasis in mammalian cells. Malignant tumor cells seem to hijack some of these mechanism to protect themselves from the acidic environment and to maintain acidity in an environment unsuitable for normal or more differentiated cells. Recent data suggest that vacuolar-type (V-type) H(+)-ATPases, that pump protons across the plasma membrane, may have a key role in the acidification of the tumor microenvironment. Some human tumor cells are characterized by an increased V-type H(+)-ATPase expression and activity, and pretreatment with proton pump inhibitors -- a class of H(+)-ATPase inhibitors -- sensitized tumor cell lines to the effect of a variety of anticancer drugs. Proton pump inhibitor pretreatment has been associated with inhibition of V-type H(+)-ATPase activity and increase in both extracellular pH and pH of lysosomal organelles. In vivo experiments in human/mouse xenografts have shown that oral pretreatment with proton pump inhibitors is able to sensitize human solid tumors to anticancer drugs. These data suggest that tumor alkalinization may represent a key target of future antitumor strategies.