The heterogeneous distribution of hypoxic regions within solid tumors renders them refractive to chemo- and radio-therapies and contributes positively to tumor invasion and metastasis. Moreover, hypoxia favors the enrichment of cancer stem cells by interacting with differentiation signals via the maintenance of stem cell properties of undifferentiated cells or via the induction of cellular dedifferentiation. The discovery of the hypoxia inducible factor 1alpha (HIF-1α) has led to the current extensive interest in the signal molecules related to tumor hypoxia and the major regulatory pathways that control the family of hypoxia-inducible factors as potential molecular targets for cancer therapeutics. Multiple approaches have been developed to circumvent hypoxia-induced resistance, such as oxygenating tumors, using radiosensitizers and more recently using bio-reductively activated pro-drugs. Recent evidence suggests that radio-sensitization has undergone a paradigm shift from compounds that enhance the effect of radiation via mimicking oxygen, to compounds that target HIF-mediated signaling pathways eventually reducing radio-resistance. In this paper, we give an overview of our recent understandings in hypoxia research, discuss the mechanisms of resistance of hypoxic tumors and of hypoxia-induced cancer stem cells and highlight the latest advances in cancer treatments that target tumor hypoxia and the resistant populations of cancer stem cells. Classical and novel radio-sensitization methods, mainly the molecular inhibition of HIFs and downstream targets and the use of hypoxia-activated drugs are compared and contrasted. Such multi-faceted targeted therapies ultimately enhance treatment outcomes and reduce normal tissue toxicity by the selective targeting of solid tumors.