Hypoxia is a universal feature of solid tumors that arises as the tumor mass outgrows stromal vascular supply. Hypoxia-inducible factor (HIF)-1, a transcription factor upregulated in hypoxia, orchestrates a range of adaptive responses that allow tumor cells to survive oxygen deprivation. Important information regarding the role of HIF-1 in tumor biology was gained from tumor biopsy studies in which HIF-1 expression was strongly associated with poor patient prognosis, and from animal studies in which genetic ablation of HIF-1 signaling retarded tumor growth. These findings motivated an intensive search for small-molecule inhibitors of the HIF-1 pathway. This review describes the progress toward the identification of specific inhibitors of HIF-1, and discuss the first examples of HIF-1-targeted therapeutics to enter clinical development. © The Thomson Corporation.