Selenium (Se) is an essential biological element and selenite is used to supplement malnutrition of Se and may also have anticancer activity. However, Se is also known as a delicate micronutrient with a narrow window of useful dose and the mechanisms for the sudden toxic effect remain unclear. Recently, we reported elsewhere that selenite was incorporated into cells via xCT, a cystine/glutamate antiporter. xCT is regulated by a stress responsive nuclear factor erythroid 2-related factor 2 (Nrf2). Therefore, we hypothesized and preliminary substantiated that the Nrf2-xCT pathway underlies the toxicity mechanism of Se. Expression of xCT mRNA was remarkably increased in MCF-7 cells after Se treatment, which may further increase Se uptake and oxidative stress. Pretreatment with xCT or Nrf2 inhibitors prevented morphological changes by releasing cells from uncontrolled feedback on Se uptake. Paradoxically, Se-induced oxidative toxicity is promoted by a runaway of stress response in Nrf2-xCT pathway. The results imply a novel mechanism by which Se accelerates its oxidative toxicity through feedback via Nrf2-xCT. This mechanism explain the elusive toxicological properties of inorganic Se, including strong cytotoxicity, high sensitivity in cancer cells, and narrowness of pharmacological dose range.