Colon cancer remains a leading cause of mortality worldwide despite the well-characterized molecular events in the adenoma-to-carcinoma sequence. There has been a strong emphasis on early detection of colon cancer, and fecal DNA-based methods have been developed to assist with early screening. Tissue-based assays have been utilized for many years to assess tumor aggressiveness and to determine prognosis and response to chemotherapeutic interventions. The most widely used serum marker for colon cancer (carcinoembryonic antigen) remains a useful modality to assess for occult disease following curative resection. Identification of tumor mutations in circulating tumor cells and microarray analysis holds a great deal of promise in the diagnosis and prognosis of patients with colorectal cancer. The inhibitors of apoptosis may be important markers to determine resistance to radiation cytotoxicity in rectal cancer. This report presents a summary of the current status of the molecular markers of colorectal cancer to establish a diagnosis, determine prognosis and chemoradiotherapeutic interventions, and assess relapse following curative surgery.