Considerable data suggest that DNA replication is involved in repeat instability in some, but not all patient tissues. Using patient-derived cell lines, we used various drugs that alter DNA replication to determine if exposure could modulate repeat instability. Data suggest that drugs that inhibit replication can modulate repeat instability in DM1 patient cell lines. Drug-induced instability was targeted specifically to the expanded disease allele, and did not affect the non-disease allele or other parts of the genome. Ongoing studies are aimed at identifying drugs that will arrest or reverse repeat expansions, with the long-term hope of arresting disease progression. A related goal is to further elucidate the underlying mechanism(s) of instability.