Hypoxia-regulated gene therapy. Hypoxia may be exquisitely exploited to achieve selective gene delivery, gene expression and bioreductive prodrug activation specifically within hypoxic tumour regions. Viral delivery vehicles can be specifically targeted to surface receptors upregulated on hypoxic cells or obligate anaerobes can be harnessed as vectors for their innate ability to colonise these regions. Making hypoxia a prerequisite for both gene expression and drug activation may reduce cytotoxicity to healthy tissues that can be achieved by combining hypoxia responsive element (HRE)-driven gene expression of a reductase gene with a bioreductive drug. This will allow the specific activation of the bioreductive drug to a free radical DNA damaging species within hypoxic cells that is free to diffuse to other hypoxic cells to exert a bystander effect. Diffusion to healthy aerobic tissues, in contrast, will result in re-oxidation of the drug to its non-toxic prodrug. HIF, hypoxia inducible factor; e-, electron.