Genomic DNA is subject to damage at such high frequencies that only with efficient DNA-repair pathways genomic stability is maintained. Research efforts of many groups over several decades have revealed the salient properties of the various DNA-repair mechanisms, but it has largely remained unclear how damage sites are localized in genomic DNA. In PNAS, Gorman et al. (1) unveil insights into the DNA-repair process called mismatch repair (MMR), which is responsible for the repair of incorrectly paired DNA bases. They use a combination of single-molecule fluorescence imaging and nanofabrication to study how different search mechanisms are used in eukaryotic MMR to find mismatches.