Multiple genetic alterations occur in melanoma, a lethal skin malignancy of increasing incidence^,. These include mutations that activate Ras and two of its effector cascades, Raf and phosphoinositide 3-kinase (PI3K). Induction of Ras and Raf can be caused by active N-Ras and B-Raf mutants as well as by gene amplification^,,. Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification^,,. Melanomas also commonly show impairment of the p16^INK4A-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways. CDKN2A mutations can produce p16^INK4A and ARF protein loss^,,,. Rb bypass can also occur through activating CDK4 mutations as well as by CDK4 amplification^,. In addition to ARF deletion, p53 pathway disruption can result from dominant negative TP53 mutations^,. TERT amplification also occurs in melanoma. The extent to which these mutations can induce human melanocytic neoplasia is unknown. Here we characterize pathways sufficient to generate human melanocytic neoplasia and show that genetically altered human tissue facilitates functional analysis of mutations observed in human tumors.