Heterogeneity in advanced colon cancer leads to different results from adjuvant chemotherapy. To identify groups of patients who may need adjuvant treatment, molecular staging and correlation with clinical data may be helpful in classifying histologically similar tumors. Colon cancer develops through a multistep process with an accumulation of multiple genetic alterations that are often the cause of a form of genomic instability. The 2 best known mechanisms of genomic instability are chromosomal instability (CIN) and microsatellite instability (MSI). The CIN phenotype is found in approximately 85% of sporadic colon cancers and is characterized by aneuploidy, multiple chromosomal rearrangements, and an accumulation of somatic mutations in oncogenes such as K-ras and tumor suppressor genes such as TP53 and APC. The MSI phenotype is associated with small insertions and deletions mainly in repetitive sequences (microsatellites) and is found in approximately 15% of cases. This instability, often referred to as high-frequency MSI (MSI-H), is caused by defects of the mismatch repair system, which is involved in repairing DNA errors that arise during DNA replication. Clear-cut correlations between the somatic genetic alterations in tumors and the clinical behavior of the tumor are rare. Only a few markers, such as MSI-H and TP53, seem to have a prognostic value. Mutations in the TP53 gene are associated with an aggressive tumor growth and subsequent reduced survival, whereas MSI-H seems to be correlated with a favorable outcome. In general, predicting biologic behavior of in particular stage III colon cancers is difficult and remains a great clinical problem.