We developed the techniques of lymphatic mapping and sentinel node (SN) biopsy to improve the management of patients with high-risk (thick and deep) primary melanoma. The SN is the first lymph node on the direct lymphatic drainage path from the primary tumor. This node is uniquely immune-modulated by the primary tumor and is the node most likely to contain the earliest stages of metastases. Accurate assessment of the SN requires careful evaluation of multiple sections removed from the areas of the node most likely to contain tumor. These sections are stained with hematoxylin and eosin and by immunohistochemistry with antibodies directed to tumor-associated markers (S-100, HMB-45, and Melan-A/MART-1) in the case of melanoma and to cytokeratins for breast cancer. Studies are in progress to determine whether molecular biology techniques will detect additional nodes that contain truly occult tumor deposits.