In melanoma, at least four major signaling abnormalities have been described. They include beta-catenin deregulation (mutation/mislocalization), p16 loss, MAP kinase activation, and Akt activation. In this review, we discuss the role of the fourth pathway, known as the reactive oxygen driven tumor. The role of reactive oxygen in tumorigenesis is likely to relate to virtually all forms of cancer, and lends itself to specific therapies. These include blockade of reactive oxygen, resulting in decreased activation of NF-kappaB, which should sensitize tumors to chemotherapy and radiation. The phenotype of the reactive oxygen driven tumor can be monitored using available markers already in use in most hospital laboratories.