Since 1970, the multifactorial pathogenesis of the deficient and heterogeneous oxygenation of transplanted murine tumors and of human cancers (including parameters determining oxygen delivery, e.g., blood flow, diffusion geometry, oxygen transport capacity of the blood) has been investigated in vivo. Hypoxia and/or anoxia was quantitatively assessed and characterized using microtechniques and special preclinical tumor models. Hypoxia subtypes were identified, and critical supply conditions were theoretically analyzed. In the 1980s, first experiments on humans were carried out in cancers of the rectum and of the oral cavity. In the 1990s, the clinical investigations were carried out on cancers of the breast and of the uterine cervix, clearly showing that hypoxia is a hallmark of locally advanced human tumors. In multivariate analysis, hypoxia was found to be an independent, adverse prognostic factor for patient survival due to hypoxia-driven malignant progression and hypoxia-associated resistance to anticancer therapy.