Hypoxia is a characteristic property of locally advanced solid tumors, resulting from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the development of hypoxia are (1) structural and functional abnormalities of the tumor microvasculature, (2) increased diffusion distances, and (3) tumor-associated and therapy-induced anemia. The oxygenation status is independent of clinical tumor size, stage, grade, and histopathological type, but is affected by the hemoglobin level. Hypoxia is intensified in anemic patients, especially in tumors with low perfusion rates. Hypoxia and anemia (most probably via worsening of tumor hypoxia) can lead to therapeutic problems, as they make solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy. In addition to more direct mechanisms involved in the development of therapeutic resistance, there are also indirect machineries that can cause barriers to therapies. These include hypoxia-driven proteome and genome changes and clonal selection. These, in turn, can drive subsequent events that are known to further increase resistance to therapy (in addition to critically affecting long-term prognosis). Treatment resistance in anemic patients can be, at least partially, prevented or overcome by anemia correction, resulting in better locoregional tumor control and overall survival of patients.