Hypoxia is a generic micro-environmental factor of solid tumours. High levels of hypoxia lead to resistance to radiotherapy, which can be targeted by adding hypoxia-modifying therapy to improve clinical outcomes. Not all patients benefit from hypoxia-modifying therapy, and there is a need for biomarkers to enable progression to biologically personalised radiotherapy. Gene expression signatures are a relatively new category of biomarkers that can reflect tumour hypoxia. This article reviews the published hypoxia gene signatures, summarising their development and validation. The challenges of gene signature derivation and development, and advantages and disadvantages in comparison with other hypoxia biomarkers are also discussed. Current evidence supports investment in gene signatures as a promising hypoxia biomarker approach for clinical utility.