Recent advances in immunomagnetic separation and flow cytometry have made the detection and characterization of circulating tumor cells (CTC) a reality. This technology has already demonstrated prognostic significance in breast and prostate cancer. In the current review, we will review the historical and current data regarding the enumeration and identification of CTC in colorectal cancer. With immunomagnetic separation techniques, CTC can reliably and reproducibly be identified within 1 to 2 cells in a 7.5 mL sample of peripheral blood. Prospective studies have demonstrated a significant adverse impact on survival with the presence of > or = 3 CTC per 7.5 mL blood. Approximately one quarter of patients with metastatic disease will be categorized in this poor prognosis group. In addition, change in number of cells on treatment has prognostic significance. While CTC enumerated through immunomagnetic separation are a clear prognostic factor for patients with mCRC, the future challenge is to study whether treatment decision-making should be impacted by their level. Low cell yield in mCRC is a potential hinderance to answering these important clinical questions at present. CTC can also be isolated and studied with flow cytometry, FISH, and RT-PCR, allowing real-time assessment of tumor biology. Future advances in this field will improve both the detection and manipulation of these cells. Improvements in detection and characterization of CTC will hopefully lead to refinement of the surgical and chemotherapeutic treatment of colorectal cancer.