Solid tumors with areas of hypoxia are the most aggressive and difficult tumors to treat and are a major reason for treatment failure. Previous attempts to treat hypoxic tumors have been largely unsuccessful and new agents are needed. The cellular response to hypoxia is controlled by the hypoxia inducible factor-1 (HIF-1) transcription factor. HIF-1 consists of an oxygen regulated alpha subunit and a constitutively expressed beta subunit, which bind and translocate to the nucleus to activate transcription of a range of genes involved in increasing glycolysis, inhibition of apoptosis and promotion of angiogenesis and metastasis. The activity of the HIF-1 complex is primarily controlled by levels of the alpha subunit and a series of mechanisms exist to control activation of the HIF-1 pathway. HIF-1alpha is over-expressed in a large number of human tumors and its over-expression correlates with poor prognosis and treatment failure. HIF-1 is therefore an important target for cancer chemotherapy. This review summarizes the literature surrounding the control of HIF-1, its role in cancer and potential drugs to target the pathway for cancer therapy.