Hematoxylin and eosin (HE) and immunohistochemical (IHC) staining have been commonly used in combination with thin serial sectioning of frozen and paraffin-embedded specimens for the detection of micrometastatic disease in the lymph nodes of patients with esophageal cancer. The application of IHC has markedly improved the sensitivity of micrometastatic disease detection in the lymph nodes beyond the capability of routine HE staining alone. Increasing the sensitivity of occult tumor cell detection in the lymph nodes using molecular-based analysis should enable a more accurate understanding of the clinical significance of various patterns of micrometastatic nodal disease. Further studies will explore the clinical significance of micrometastases or isolated tumor cells in the lymph nodes in patients with esophageal cancer. Individualized selective and modified lymphadenectomy targeting sentinel nodes for clinically NO early esophageal cancer may become feasible and clinically useful as a less invasive surgical procedure.