While the most significant prognostic and predictive marker in the management of colorectal cancer patients is cancer cells in regional lymph nodes, approximately 30% of patients whose lymph nodes are ostensibly free of tumor cells by histopathology ultimately develop recurrent disease reflecting occult metastases. Molecular techniques utilizing highly specific markers and ultra-sensitive detection technologies have emerged as powerful staging platforms to establish prognosis and predict responsiveness to chemotherapy in colorectal cancer patients. This review describes the evolution of the tumor suppressor GUCY2C as a prognostic and predictive molecular biomarker that quantifies occult tumor burden in regional lymph nodes for staging patients with colorectal cancer.