The cellular machinery that replicates our chromosomes is not perfect, and permanent mutations can be introduced into our genomes if replication errors are not corrected soon after passage of the replication fork. Cells correct these errors by employing Mismatch Repair (MMR) proteins, which survey the genome for mispaired bases and correct them before they can lead to an accumulation of genetic damage. As with HR, the proteins involved in MMR are conserved throughout evolution. MMR is essential for maintaining genome integrity, and defects in MMR proteins lead to highly elevated rates of spontaneous mutation. For example, MutS is an evolutionarily conserved component of the bacterial MMR system, and in its absence there is a 100- to 1000-fold increase in mutation frequency. Similarly, defects in the eukaryotic Msh2 protein (MutS Homolog 2) lead to an accumulation of genetic damage and predispose humans to hereditary nonpolyposis colorectal carcinoma (HNPCC), a common form of cancer that affects nearly 1 in 200 individuals. MutS, and its eukaryotic homologs, are responsible for locating mismatched bases and initiating the first steps in the repair process. However, it is unclear precisely how these proteins survey the genome for mispaired bases or how they initiate subsequent steps in the repair pathway - in fact, these details of the reaction have been a point of controversy in the DNA repair field. We are currently using TIRFM to determine precisely how the MMR proteins survey DNA for damage and what they do once regions of damage are located.