This detailed book contains techniques to explore the unusual properties of the peculiar microsatellites known as trinucleotide repeats. Beginning with technical challenges raised by secondary structure-forming repeats and their propensity to contract and expand over time, the book continues with genetic screens in Saccharomyces cerevisiae, experimental systems to study trinucleotide repeat instability in human cells, dedicated experimental systems in appropriate cell types, as well as gene therapy approaches using the CRISPR-Cas family of endonucleases. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.