During the last 2 decades, the development and wide acceptance of SLN biopsy have affected the management of melanoma profoundly. This technique represents a considerable improvement in the ability to evaluate the tumor status of the regional lymph node basin, which is the most important predictor of survival in patients who have melanoma. Histopathologic and molecular assessment of the SLN has enhanced the detection of clinically occult nodal metastases, thereby distinguishing patients who might benefit from immediate lymphadenectomy from those for whom this procedure is unlikely to be helpful. This technique also identifies patients who would be candidates for clinical trials of adjuvant therapy. Centers can offer SLN biopsy without routine CLND once they reach a level of proficiency that usually corresponds to a learning phase of 55 cases. The role of molecular technology in the identification and analysis of the SLN remains to be established. Although molecular evidence of SLN metastasis has been identified in patients who have early-stage melanoma, its clinical relevance cannot be determined until marker selection is improved. The markers presently under study lack sensitivity and specificity. The role of molecular biomarkers can be validated only through large, multicenter, randomized. controlled trials such as the MSLT-II, a trial that will determine the benefit of multimarker RT-PCR assay in SLN specimens. SLN offers a promising future in staging lymph nodes and will improve the management of patients who have melanoma. Although SLN biopsy has become widely accepted as a minimally invasive technique of staging regional lymph nodes, its use in patients who have melanoma continues to be challenged. The future of SLN biopsy holds promise if prospective multicenter trials confirm a survival benefit for SLN biopsy as compared with watch-and-wait observation.