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In dividing cells, DNA replication is carried out by high-fidelity DNA polymerases that, in addition to nucleotide selectivity, possess exonucleolytic proofreading activities. Biosynthetic errors that escape proofreading are substrates for DNA mismatch repair (MMR), a repair pathway conserved from bacteria to humans. Loss of MMR results in a substantial increase in the rate of mutation and is the underlying genetic defect in Lynch syndrome hereditary colorectal cancer. Epigenetic silencing of key MMR genes contributes to a subset of spontaneous tumors. This review summarizes our current knowledge of the mechanism of MMR in mammalian cells, its role in DNA-damage signaling, and its contribution to the maintenance of genome stability and tumor suppression.