Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD) constitute a family of sun-sensitive human diseases (1). They are caused by mutations in the components of the nucleotide excision repair (NER) system and in the postreplication repair system involving the low-fidelity polymerase H (also known as XP variant or XPV). XP was initially recognized as a disease involving a genetic predisposition to extremely high levels of skin carcinogenesis from solar exposure. The relationship between DNA damage from solar UVB exposure and deficiencies in repair, leading to mutagenesis, genetic instability, and eventual carcinogenesis, provides a deceptively simple explanation for the major clinical features of XP and has provided a paradigm for environmentally induced human cancer. These diseases are, however, much more complex at all levels (1, 2), as the new report in this issue by Murai et al. (3) indicates (Fig. 1). NER has two main pathways: GGR and TCR. Global repair involves the genes XPC and XPE and is generally slower and modulated by p53 (4), which also modulates the pol H pathway (5, 6). TCR results in a more rapid repair of the transcribed strand of expressed genes, and involves the two CS genes (CSA, CSB), several of the XP genes (especially XPA, -B, and -D), and the mismatch repair system (1). Some of the genes are involved in both pathways, especially XPA. The XPG endonuclease is also a cofactor for a glycosylase (endonuclease III, encoded by nth) that acts on oxidative damage (7). Mutations in XPB and XPD also can give rise to diseases that combine one or more of the three main disorders, XP, CS, and TTD, depending in part on the precise site of the mutations in the genes.