The presence of lymph node metastasis is the best predictor of disease progression and overall survival in patients who have melanoma. Lymphatic mapping and selective lymphadenectomy allows directed pathologic analysis of the node or nodes most likely to have metastatic disease. To diagnose metastatic disease in SLNs reliably requires a coordinated effort by nuclear medicine physicians, surgeons, and pathologists. Errors may occur if quality assurance is not emphasized at any point during the process. This, along with the presence of occult metastatic disease, may lead to disease recurrence and progression, even when SLN histologically are free of disease. Molecular up-staging of occult malignant disease has the potential to provide important information to facilitate the diagnosis, surveillance, and treatment of cancer. The detection of occult tumor cells in SLNs and blood provides a powerful tool for assessing early regional and systemic disease spread in patients who have AJCC stage II and III-not only melanoma but also other solid tumors. The use of varying panels of markers from different laboratories has hampered the interpretation of data and made it difficult to unravel the merits of molecular up staging. Molecular approaches have made a major impact on the field of infectious disease and should one day be of equal usefulness in the diagnosis of cancer.