Hereditary forms of colorectal cancer (CRC) account for up to 5% of total cases. Familial adenomatous polyposis (FAP) is an autosomal dominant condition affecting nearly 1 in 5000 people and accounts for only about 1% of all CRCs. It is characterized by the progressive development of hundreds to thousands of adenomatous colon polyps. The gene associated with FAP (APC) contains 15 exons in the coding region. A scanning approach for large genes is reasonable, but some standard techniques have limited analytical sensitivity. The method described here, using DHPLC as mutation scanning approach for medium-throughput DNA sequence analysis, is largely considered to be the gold standard for point mutation analysis, and can be optimized for high-throughput testing. Detection of deletion and duplication mutations refractory to sequencing have been described using real-time quantitative PCR for dosage analysis. Technical strategies for mutation detection in the APC gene are presented in this chapter.