Metastatic melanoma patients have a dismal prognosis with poor responsiveness to chemotherapy, radiation therapy and current immunotherapy regimens and a median survival of less than six months. Novel therapies directed at melanoma-selective molecular targets are urgently needed. Based on the frequent constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway in malignant melanomas and the selective inhibition of MAPK signaling by anthrax lethal factor which proteolytically cleaves MAPK kinases, anthrax lethal toxin may be a useful agent for patients with metastatic melanoma. Anthrax lethal toxin consists of two proteins--protective antigen and lethal factor. These two proteins have been separately produced in good yields and in high purity. The three-dimensional structures of these proteins have been solved, and their molecular mechanisms of cell binding and action determined. Preclinical studies with anthrax lethal toxin show sensitivity of malignant melanoma cell lines in tissue culture and anti-tumor efficacy in melanoma xenograft models. Additional studies to define the maximal tolerated doses and dose-limiting toxicity of anthrax lethal toxin in rodent and primate models should pave the way for phase I studies testing the efficacy of the anthrax lethal toxin in patients with metastatic melanoma.