The bidirectional interactions between tumor cells and the so-called "host reactive stroma" play a critical role in most of the events characterizing tumor progression and distant organ colonization. This review discusses critical components of tumor environment involved in tumor cell dissemination. More specifically, it addresses some of the experimental evidences providing that acidity of tumor environment facilitates local invasiveness and metastasis formation, independently from hypoxia, with which acidity may be associated. Besides, acidity renders tumor cells resistant to radiation therapy and chemotherapeutic drugs. Therefore, this review examines the strategies for raising the low extracellular pH of tumors that might have considerable potential in cancer therapy.