Novel molecularly targeted therapies aim at exploiting oncogenic and non-oncogenic alterations that epitomize potential vulnerable aspects of tumorigenesis, with the hope to ultimately target cancer cells and spare normal tissues. Hypoxia, a decrease in tissue oxygen levels, is a feature of the tumor microenvironment that has attracted considerable interest for its potential contribution to increasing the tumorigenicity of cancer cells, by selecting more aggressive and metastatic clones and by activating pathways that contribute to cancer cells survival, all of which may have important therapeutic implications. In this article, we discuss how two therapeutic strategies, which have been developed over the last few years to target aspects dependent on or associated with intratumor hypoxia, may provide the rationale for a novel combination strategy aimed at blocking compensatory circuits that maintain cancer cells survival and propagate the cancer phenotype. We hypothesized that concurrent inhibition of HIF-1 and VEGF, which are mechanistically linked to intratumor hypoxia, represents a logical therapeutic combination that may find applications in a number of solid tumors, irrespective of their underlying genetic alterations. Indeed, intrinsic limitations of HIF-1 inhibitors and mechanisms of acquired resistance to anti-VEGF therapies may counter-balance each other in combination approaches that block vicious compensatory pathways exploited by cancer cells to overcome environmental stresses.