Nodal status in melanoma is a critically important prognostic factor for patient outcome. The survival rate drops to <10% when melanoma has spread beyond the regional lymph nodes and includes visceral involvement. In general, the process of melanoma metastasis is progressive in that dissemination of melanoma from the primary site to the regional lymph nodes occurs prior to systemic disease. The goal of this review article is to describe melanoma as a clinical model to study cancer metastasis. A future challenge is to develop a molecular taxonomy to subgroup melanoma patients at various stages of tumor progression for more accurate targeted treatment. J. Surg. Oncol. 2011;103:538–549. © 2011 Wiley-Liss, Inc.