Over time, we accumulate genetic damage that accelerates the aging process, increasing the risk of carcinogenesis. DNA is continually challenged by genotoxic factors that affect its fragile structure, inhibiting cell functions. To meet this challenge, cells have evolved a number of overlapping DNA repair mechanisms that detect and repair DNA damage. Nucleotide excision repair (NER) is a major DNA repair mechanism that cells employ to remove a wide class of bulky, DNA-distorting lesions from the genome. The importance of NER defects in man is illustrated by rare syndromes that either show increased cancer predisposition or dramatic features of accelerated aging, including depletion of fat depots. However, with the exception of cancer and aging, the links between defects in NER and the rapid onset of developmental defects in humans are not well understood.