Increasingly, the tumor microenvironment and hypoxia are being studied as potential prognostic factors in prostate cancer given their effects on the hypoxia inducible factor-1α and vascular endothelial growth factor signaling pathways. Based on immunohistochemical studies using hypoxic cell markers and direct oxygen-electrode measurements, clinically relevant levels of hypoxia are detected in 30–90% of prostate cancers. Exciting new data suggest that hypoxia can alter cell-cycle checkpoints and DNA repair within the prostate epithelium, thereby driving genetic instability and tumor aggression. Novel therapies designed to target the hypoxic response and resulting defective DNA repair may therefore be effective as chemoprevention agents or as adjuncts to surgery, radiotherapy and chemotherapy to improve clinical outcome.