DNA repair of bulky adducts is essential for a normal life, as demonstrated by the existence of rare but dramatic diseases, such as xeroderma pigmentosum (XP), associating DNA repair deficiency and a high cancer proneness. It is plausible that small variations in the efficacy of repair in the normal population may facilitate cancer development in exposed individuals. In order to check this hypothesis, associations between single nucleotide polymorphisms (SNPs) in key genes and some frequent human cancers have been researched. Among the repair proteins, the XPD protein is interesting because it is a major player in the nucleotide excision repair pathway and is also involved in transcription initiation and in the control of the cell cycle and apoptosis. Several SNPs have been described in the ERCC2/XPD gene, but three in particular have been studied: the C-->A silent polymorphism (Arg156Arg) in exon 6, the G-->A polymorphism leading to Asp312Asn in exon 10 and the A-->C polymorphism leading to Lys751Gln in exon 23. We review here the epidemiological studies examining whether these polymorphisms are correlated with reduced DNA repair efficiency (analysed using different assays), their influence on the development of cutaneous carcinomas and smoking-related cancers and their possible interactions with environmental exposures.