The central component of hypoxia sensing in the cell is the hypoxia-inducible factor (HIF) transcriptional complex. HIF activity is deregulated in many human cancers, especially those that are highly hypoxic. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Overexpression of HIF-α, the regulatory subunit of HIF, is associated with increased vascular density, severity of tumour grade, treatment failure and a poor prognostic outcome with conventional therapies. Therefore HIF is an attractive, although challenging, therapeutic target, and several different strategies have been developed to target HIF directly or indirectly in recent years. This review outlines the preclinical and clinical advances in this arena and discusses which cancers may benefit from HIF-targeted therapy.