Both endogenous metabolism and exogenous sources (such as alcohol consumption) can yield reactive aldehydes within the body that can ultimately damage our DNA. Their potential toxicity is encountered by two serial protection barriers, also referred to as two-tier protection. The first tier comprises the enzymatic detoxification of these molecules, such as oxidation of acetaldehyde catalyzed by the ALDH2 protein. The second tier is specific DNA damage repair and takes action when aldehyde-induced DNA damage has already occured. In the human disease Fanconi anemia, an inherited deficiency of DNA interstrand crosslink repair means a failure of second-tier protection and promotes genomic instability, eventually leading to developmental defects, bone marrow failure and an increased risk for cancer.