Melanoma is a highly metastatic cancer that accounts for the majority of skin cancer deaths. Unfortunately, very few improvements have been made during the last 20 years in the management of melanoma metastases, which is the major cause of melanoma deaths. Therefore, identification of molecular targets that can be exploited in the clinic to treat metastatic disease is desperately needed. The KISS1 metastasis suppressor gene has emerged as a promising molecular target for the management of metastatic disease. This review compiles data regarding the molecular and biochemical properties of KISS1 and its cognate receptor, focusing on the properties believed to be most pertinent to the use of KISS1 in the clinical setting. In addition, clinical data that supports KISS1 as having a dual role as a prognostic indicator and a therapeutic target for the management of metastatic disease will be highlighted.