In melanoma patients, the sentinel node biopsy (SNB) procedure is a highly accurate staging method, and the tumor-harboring status of the sentinel node (SN) is the most important prognostic factor for patients with early stage disease. For the SN to provide accurate prognostic information, however, it is essential that all "true" SNs are removed and examined diligently. Pathologists should examine multiple hematoxylin-eosin and immunohistochemically stained sections from each SN, but it is unclear from the currently available evidence what is the most appropriate sectioning and staining protocol. Relevant factors to consider include the accuracy of the procedure, the time, labor, and costs involved, and clinical follow-up data which are likely to vary between institutions; hence, individual protocols should be developed locally by pathologists in consultation with their surgical colleagues. At the Sydney Melanoma Unit, four sequential sections of both halves of each SN are examined. The first and fourth sections are stained with hematoxylin-eosin, the second section is stained for S-100 protein, and the third section is stained for HMB-45. Pathologists should not only identify the presence of melanoma metastases within the SN, but also record the size of the largest metastatic focus, tumor penetrative depth (measured from the inner margin of the node capsule to the deepest tumor cell within the SN), and the percentage nodal cross-sectional area involved (as measured on the slides). Potential diagnostic pitfalls in SN evaluation include the misinterpretation of nevus cells, macrophages, or antigen-presenting interdigitating dendritic cells as melanoma. Careful assessment of the morphologic characteristics of the cells and their immunohistochemical profile should prevent misdiagnosis. Routine frozen section examination of SNs from melanoma patients is not recommended. The utility of ultrasound to detect SN metastases (confirmed by fine needle biopsy) is currently being investigated. Whereas potentially this may avoid the need for formal sentinel lymphadenectomy and histopathologic evaluation in some patients, the lack of sensitivity of currently available ultrasound technologies to detect the small micrometastases (<2 mm in diameter), that are typically present in most melanoma patients with a positive SN, limits its current role. In the future, other techniques, such as the use of carbon particles or antimony analysis, may better localize the site of metastases within SNs and permit more focused and efficient pathologic examination of SNs. At present, the role of nonhistopathologic methods of SN evaluation, such as reverse transcription polymerase chain reaction (RT-PCR) and magnetic resonance spectroscopy, remains unclear, and these techniques require further evaluation.