Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. It is caused by a pathologic expansion of the CAG trinucleotide repeat sequence within the huntingtin gene (HTT) on chromosome 4. This expansion leads to the production of an abnormally long and compromised mutant huntingtin mRNA and protein, which have been linked to neuronal dysfunction and cell death predominantly within the basal ganglia and cortex. While the expanded CAG repeat is the primary genetic determinant of HD, somatic instability (SI) in the size of the repeat sequence has emerged as a critical factor in the onset and progression of the disease. SI refers to the dynamic nature of CAG repeat expansions or contractions occurring within the affected individual's lifetime and is a primary driver of the predicted age of onset in HD. Genome-wide association (GWA) studies have identified an array of genes linked to changes in the age of onset for motor dysfunction and other phenotypic milestones associated with HD onset and progression. Within this list of genes, components of the DNA mismatch repair (MMR) pathway were disproportionately represented. In combination with earlier data from animal models of HD, the human genetic data pointed to a central role for this pathway as effectors of somatic instability and by extension in the timing of disease onset. Therefore, these MMR pathway proteins may serve as attractive targets for therapeutic intervention designed to delay SI and the onset of HD signs and symptoms.