Mutations are rare events, occurring spontaneously at a frequency of 1 per 109-1010 base pairs per cell division. 1, 2 Nucleotide misincorporation during DNA synthesis yields noncomplementary base pairs or mismatches within the DNA helix, which if uncorrected are fixed as mutations during the subsequent round of DNA replication. Mutations can also arise via incorporation of chemically damaged nucleotides or by incorporation of an undamaged nucleotide opposite a damaged base within the template strand. 3-5 Strand slippage or formation of unusual secondary structures within DNA, especially within repetitive sequences, can also result in mutations when processed aberrantly during replication, recombination, or repair. 6-9 Base pair geometry and the nature of the DNA polymerase involved result in an error rate of 10-4-10-5 at the nucleotide insertion step of DNA synthesis. 10 In the event of incorrect insertion, the proofreading exonuclease associated with some DNA polymerases edits the mistake, permitting the enzyme to make a second attempt at correct synthesis. Nucleotide selection and editing in this manner confers an error rate of∼ 10-7 per bp per replication. Mistakes that escape these fidelity devices are corrected by mismatch repair, further elevating fidelity 50-1000-fold. In this pathway, a noncanonical base pair is recognized by a MutS homologue, which in conjunction with a MutL homologue initiates replacement of the offending nucleotide on the newly synthesized strand by an excision repair mechanism. The activities that participate in this process have been best characterized in Escherichia coli, although substantial information is now available on the yeast and human systems. In addition to replication errors, mismatches arise as a natural consequence of genetic recombination when the heteroduplex intermediate spans genetic differences between the recombining helices, and such mispairs can be processed by the repair system. 11, 12 A variety of base pair anomalies resulting from DNA damage are also subject to processing by mismatch repair. These include base pairs containing O6-methylguanine, 13-17 8-oxoguanine, 18, 19 carcinogen adducts, 20 UV photo products, 21-23 and cisplatin adducts. 16, 24, 25