Colorectal cancer results from an accumulation of mutations in tumor suppressor genes and oncogenes. An additional defining characteristic of colorectal cancer is its genetic instability. Two main types of genetic instability have been identified. Microsatellite instability leads to an increased point mutation rate, whereas chromosomal instability refers to an enhanced rate of accumulating gross chromosomal aberrations. All colon cancer cell lines are genetically unstable. An interesting question is whether genetic instability arises early in tumorigenesis. An early emergence of genetic instability could drive most of the somatic evolution of cancer. Here, we review mathematical models of colorectal tumorigenesis and discuss the role of genetic instability.