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This review provides a comprehensive overview of the evolving role of minimal residual disease (MRD) for patients with Colon Cancer (CC). Currently, the standard of care for patients with non-metastatic CC is adjuvant chemotherapy (ACT) for all patients with stage III and high-risk stage II CC following surgical intervention. Despite a 5-20% improvement in long-term survival outcomes, this approach also results in a significant proportion of patients receiving ACT without any therapeutic benefit and being unnecessarily exposed to the risks of secondary side effects. This underscores an unmet clinical need for more precise stratification to distinguish patients who necessitate ACT from those who can be treated with surgery alone. By employing liquid biopsy, it is possible to discern MRD enabling the categorization of patients as MRD-positive or MRD-negative, potentially revolutionizing the management of ACT. This review aimed to examine the heterogeneity of methodologies currently available for MRD detection, encompassing the state-of-the-art technologies, their respective advantages, limitations, and the technological challenges and multi-omic approaches that can be utilized to enhance assay performance. Furthermore, a discussion was held regarding the clinical trials that employ an MRD assay focusing on the heterogeneity of the assays used. These differences in methodology, target selection, and performance risk producing inconsistent results that may not solely reflect biological/clinical differences but may be the consequence of the preferential use of particular products in studies conducted in different countries. Standardization and harmonization of MRD assays will be crucial to ensure the liquid revolution delivers reliable and clinically actionable outcomes for patients.