The worldwide incidence of malignant melanoma has been increasing during the past decade and is a public health concern because this disease accounts for up to 90% of deaths from cutaneous malignancies. It remains a devastating disease with few therapeutic options once in an advanced stage. Current methods of detection, prognostication, and monitoring of melanoma focus on clinical, morphologic, and histopathologic characteristics of measurable tumor. Although this information provides some insight into disease behavior and outcome, melanoma is still an unpredictable disease. Significant effort has been put into finding an informative serologic biomarker. However, the marker remains elusive, and investigations continue. Using the PubMed database, we reviewed the published literature on serologic melanoma biomarkers and present a synopsis of the extensive investigations that have been performed thus far, provide some insight into why most have failed to become incorporated into routine clinical use, and present an overview of innovative methods currently being explored.