Peroxides have been used in tooth whitening for more than 100 years. Current peroxide-containing whiteners can be classified into three categories: (1) those containing high concentrations of peroxides for professional use only; (2) materials dispensed by dentists and used by patients at home; and (3) over-the-counter products available directly to consumers for home use. Hydrogen peroxide (H2O2) and carbamide peroxide are the most commonly used active ingredients in these whiteners. Both peroxides have long been used safely in oral health products and are accepted by the US Food and Drug Administration. However, questions have been raised regarding the safety of at-home whiteners because the peroxides appear to constitute a new use. Substantial differences exist in the manner of application between at-home whiteners and oral health products. In addition, tooth whiteners are a mixture of various ingredients; possible interactions may occur because of the active nature of peroxides. Therefore, the safety evidence for peroxide-containing whiteners is considered inadequate. This paper will review the history of using peroxides for tooth whitening, the toxicology of H2O2 and carbamide peroxide, and available information on the safety of whiteners. The rationale and approaches for evaluating biological properties of peroxide containing whiteners are also discussed.