Background/Objectives: Complete mesocolic excision (CME) has recently been proposed as a radical operation for the treatment of colon cancer. Increasing evidence suggests a survival benefit from this operation, although the exact reasons for this remain largely unknown. Methods: We have undertaken a comprehensive review of the literature in PubMed and Embase databases, examining the potential mechanisms explaining this oncologic benefit. Results: Complete mesocolic excision with central vascular ligation appears to improve the rates of radial margin negativity and is associated with increased lymph node yield and improved staging for colon cancer patients by removal of apical lymph nodes and removal of skip metastasis. The en bloc removal of the cancer-related mesentery along the interfascial plane between the mesocolon and retroperitoneal structures removes en bloc tumor deposits that appear to have a significant negative effect on cancer prognosis, irrespective of lymph node status. CME is associated with decreased rates of local recurrence and improved disease-free and overall survival. The existing literature suffers from a lack of data on molecular pathology and integration of prognostic pathologic factors such as tumor deposits in patients undergoing complete mesocolic excision. Conclusions: CME confers significant benefits in terms of local control of the disease and improves cancer-specific survival. Further research on the matter is necessary to incorporate prognostic pathologic and molecular parameters.