Patients with high-risk (thick, deeply invasive) primary melanoma were, in the past, managed by wide local excision and elective node dissection or wide local excision alone, with subsequent lymphadenectomy if the regional nodes developed clinically detectable metastases. We recently developed a more logical approach called selective lymph node dissection. To be effective, this requires close collaboration of surgeons, pathologists, and nuclear medicine physicians. The draining lymph node basin is identified preoperatively by lymphoscintigraphy. During surgery, a marker dye (isosulfan blue) and radioactive technetium labeled albumin are injected intradermally around the primary melanoma and the afferent lymphatics are followed up to the first lymph nodes of the ipsilateral regional nodal basin. The surgeon excises the blue-colored and maximally radioactive sentinel nodes and the pathologist critically evaluates these for the presence of a metastatic tumor. If the sentinel nodes are tumor free, no further nodal dissection is undertaken; if a tumor is present, a complete dissection of the nodal basin is performed. We have examined 1,119 sentinel lymph nodes from 669 patients treated by selective lymph node dissection. We identified melanoma cells in sentinel nodes from 126 patients (17.8%). A single node contained tumors in 67% of patients, 2 nodes were positive in 25%, and the remaining 12% of patients had three tumor-containing nodes. Melanoma cells were dispersed singly or in variably sized groups, usually in the peripheral nodal sinus. In around 40% of patients, immunohistochemistry is required to identify minute numbers of tumor cells. With experience, pathologists identify tumors in hematoxylin and eosin (H&E) preparations in an increasing proportion of lymph nodes. Tumor cells are more frequent in the sentinel nodes of patients with primary tumors of deeper Clark level and greater Breslow thickness. Tumor cells must be discriminated from capsular nevus cells, interdigitating dendritic leukocytes, macrophages, and intranodal neural tissues.