Melanoma is a prevalent and deadly disease with limited therapeutic options. Current prognostic factors are unable to adequately guide treatment. Circulating tumor cells are a disease-specific factor that can be used as a prognostic variable to guide therapy. Most research to date has focused on identification of circulating tumor cells using various methods, including polymerase chain reaction. These techniques, however, have poor sensitivity and variable specificity and predictive significance. A recently developed technology to identify circulating tumor cells is the CellSearch system. This system uses immunomagnetic cell labeling and digital microscopy. This technology may provide an alternative method to identify circulating tumor cells in patients with advanced-stage melanoma and function as a prognostic factor. We review the literature on circulating tumor cells in melanoma and present data collected at our institution using the CellSearch system in nine patients with stage III or IV melanoma.