The thioredoxin system is one of the key antioxidant systems in the cell and is crucial for cell survival. It is comprised of thioredoxin and thioredoxin reductase and plays important roles in maintaining the redox homeostasis within the cell. The thioredoxin system is upregulated under conditions of oxidative stress to help re-establish the redox environment. This induced expression is mainly regulated through the action of regulatory elements present in their promoters, especially the antioxidant responsive element (ARE) via binding of the Nrf-2 transcription factor. The regulation of the thioredoxin system in response to a decrease in oxygen tension (hypoxic stress) is still not well known, although it is generally accepted as being up-regulated during hypoxia. The thioredoxin system is highly expressed in cancer cells, especially in more aggressive and therapeutic resistant cancers. The oxygen supply to a tumor is unstable due to abnormal vascular growth and this leads to a tumor oxygen environment that is constantly switching between hypoxic and oxidative stress, caused by the re-oxygenation step. Therefore, an understanding of how the expression of thioredoxin system is regulated in response to the different oxygen conditions occurring in cancers may aid in elucidating the link between the thioredoxin system and cancer progression.