Sentinel lymphadenectomy is gaining increasing popularity in the staging and treatment of patients with melanoma at risk for metastases. As a result, pathologists are encountering these specimens more frequently in their daily practice. The pathologic status of the sentinel lymph node is pivotal to the patient's care because it provides staging information that dictates the need for further therapy, and therefore detailed pathologic assessment is warranted. A standard pathology protocol to handle these nodes has been developed at our institution and involves complete submission of all tissue with routine use of immunohistochemical staining for S-100 protein. By using this protocol, 838 sentinel lymph nodes from 357 patients have been examined, and metastases were found in 16% of patients. Although the metastasis was clearly seen on sections stained with hematoxylin and eosin in 55% of the positive patients, the immunostain showed metastatic disease not appreciable on initial hematoxylin and eosin screening in an additional 28 lymph nodes (45% of node-positive patients). Intraoperative touch preparation cytology may be used as an adjunct technique in sentinel lymph nodes grossly suspicious for metastatic disease. This technique has been performed on 23 sentinel lymph nodes, with no false positives and an overall sensitivity of 62%. The thorough pathologic evaluation of sentinel lymph nodes in patients with malignant melanoma requires complete submission of all tissue, routine use of immunohistochemistry, and touch preparation cytology in selected cases.