Although patients diagnosed with melanoma of </= 1.00 mm thickness have a relatively good cure rate, the prognosis for patients with locally advanced and metastatic melanoma is grave. The discovery of new and effective therapies for this disease depends in large part on molecular studies that will resolve why advanced-stage melanoma is refractory to conventional chemotherapy and radiation therapy. To identify genes that have important functions in advanced-stage melanomas, in particular, in melanoma-infiltrated lymph nodes, which are not well characterized at the molecular level, we generated a LongSAGE library from a melanoma-positive lymph node, and subjected melanoma-infiltrated lymph nodes to protein expression profiling. The data document that the molecular signature of melanoma, which has spread to regional lymph nodes, is very similar to the molecular signature of primary melanomas. Equally important, we provide evidence that the ubiquitin-conjugating enzyme, Ubc9, is expressed at high levels in melanoma-positive lymph nodes, and that it plays a crucial role in preventing advanced-stage melanomas from undergoing chemotherapy-induced apoptosis.