Colon cancer results from the accumulation of genetic alterations. Genomic instability creates a permissive state in which a potential cancer cell is allowed to acquire enough mutations to become a cancer cell. Several forms of genomic instability are common in colon cancer: microsatellite instability (MSI), chromosome instability (CIN), and chromosome translocations. MSI occurs in approximately 15% of colon cancers and results from inactivation of the mutation mismatch repair (MMR) system secondary to either MMR gene mutations or hypermethylation of the hMLH1 promoter. It promotes tumorigenesis by generating mutations in target genes that possess coding microsatellite repeats, such as the transforming growth factor-β receptor type II gene. CIN occurs in most other colon cancers and leads to a different pattern of gene alterations that culminate in tumor formation. It seems to result from mutations in genes that control mitosis, DNA damage repair, centrosome structure and function, and other fundamental processes in DNA replication. The clinical significance of genomic instability is now under investigation, and it is hoped that this research will soon yield results that have an immediate effect on the treatment of colon cancer.