Understanding the biology of cancer is the key to understanding its behavior. Stage II colon cancers represent a unique treatment challenge for medical oncologists because they contain a very heterogeneous group of tumors with a wide range of recurrence risks after resection. Defining these differences in biology can help to explain differences in behavior. To this end, gene signatures have been developed to define various prognostic groups beyond the clinicopathologic features alone. Adjuvant chemotherapy for stage II colon cancers as a group has not shown survival advantage in clinical trials. Future research to develop gene signatures to predict a group that will benefit from adjuvant chemotherapy will be helpful in the clinical decision-making process. The purpose of this review is to present the prognostic gene signatures currently available for use, those in development, and their utility in stratifying recurrence risk in stage II colon cancer patients.