Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases resulting in hypoxia. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites. The key regulator of hypoxia-induced angiogenesis is the transcription factor hypoxia inducible factor (HIF)-1. Multiple HIF-1 target genes have been shown to modulate angiogenesis by promoting the mitogenic and migratory activities of endothelial cells. Because of this, hypoxia-induced angiogenesis has become an attractive target for cancer therapy, however the mechanisms involved during this process and how best to target it for cancer therapy are still under investigation. This review will cover the current understanding of hypoxia-induced tumor angiogenesis and discuss the caveats of hypoxia-targeted antiangiogenic therapy for the treatment of cancer.