As an expanding tumor conquers space within the host, it calls out for an increased oxygen supply. This demand is rarely matched by tumor blood vessels because neo-angiogenesis generates a structurally aberrant and functionally impaired vasculature. As a result of this unbalance, tumor progression is invariably associated with cancer cell hypoxia. Insufficient oxygenation appears to have opposing effects on cancer biology: on one hand, it limits tumor cell division; on the other, it selects for more malignant cells and it induces a series of cellular adaptations that sustain and foster tumor invasion. When designing a therapeutic strategy, how should we resolve this dichotomy? Should we cut oxygen supply, thereby halting neoplastic expansion, or should we let the tumor breathe, in order to prevent its malignant conversion?