DNA excision repair pathways, including the nucleotide excision repair (NER) and the base excision repair (BER) pathways, play significant roles in maintaining genomic stability. However, these pathways are found to be responsible for therapeutic resistance to cancer therapies causing DNA damage. Platinum-containing drugs are important therapies for various solid tumors. Genetic polymorphisms in NER and BER genes have been identified, and some have been correlated to altered clinical outcome to platinum-based chemotherapies. Here I studied the genetic polymorphisms in the NER genes, ERCC1 and XPD, and the BER genes, XRCC1 and PARP1, and found that the polymorphic variants had significantly higher frequencies in European Americans (EAs) for ERCC1 N118N (p<0.000001), XPD K751Q (p=0.006675), XRCC1 R399Q (p<0.000001) and PARP1 V762A (p=0.000001), compared to those in African Americans (AAs), which may reflect a mild reduction in DNA excision repair function in EA population. However, these polymorphisms were not associated with risk of prostate cancer or the clinical outcome of radiation therapy in prostate cancer in EAs. I also investigated the functional consequences of the most well studied NER polymorphism ERCC1 N118N (500C>T) by introducing the ERCC1 cDNA clones containing either the C or T allele into an ERCC1 deficient cell line UV20. However, neither the ERCC1 expression levels nor the cellular sensitivity to platinum drugs were affected by this silent mutation. These data suggests that the N118N itself does not contribute to the phenotypic differences in ERCC1, but rather this polymorphism may be linked to other causative variants or haplotypes. Therefore, I examined 4 polymorphisms in ERCC1, including rs3212948 (G>C), rs3212950 (C>G) in intron 3, and rs3212929 (T>G) in the 5' UTR, in addition to N118N (500C>T), and found that the haplotypes of these polymorphisms were associated with risk of skin melanoma, indicating the potential functional significance of other ERCC1 polymorphisms. Understanding the functional significance the genetic polymorphisms in DNA excision repair genes may facilitate the administration of personalized medicine.