Recent studies have indicated that in ∼35% of all colorectal cancer (CRC) cases, the CRC was inherited. Although a number of high-risk familial variants have been identified, these mutations explain <6% of CRC cases; therefore, further genome-wide scans will need to be conducted in the future. There are two popular approaches to genome-wide scans, namely linkage and association. The linkage approach utilizes several hundred markers (typically between 300 and 500 markers) throughout the genome and identifies candidate regions shared among affected family members. Candidate regions are then scrutinized for the presence of susceptibility loci. Linkage studies require no prior information and can provide new avenues for future research, but the regions identified are often large and include many candidate genes. The second and more recent approach is the genome-wide association study (GWAS) in which hundreds of thousands of markers called single nucleotide polymorphisms (SNPs) are used to identify the SNPs associated with traits of interest by employing family-based or case-control association methods. GWAS studies require no prior information and, because they use hundreds of thousands of SNPs, they can target specific candidate genes and/or narrow regions for investigation. Study design considerations, methodology, and the execution of linkage and genome-wide association studies that use both family and case-control designs are covered in this chapter.