The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a Δ2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RAS V12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate withp53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising in INK4a Δ2/3−/− mice, and whether tumor-associated mutations emerge in the p16 INK4a-RB pathway in such melanomas. Here, we report that p53inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on the INK4a Δ2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G 1/S transition, including c-Myc, cyclin D1, cdc25a, and p21 CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16 INK4a profoundly reduced the growth of Tyr-RASINK4a Δ2/3−/− tumor cells but had no effect on tumor cells derived from Tyr-RAS p53−/− melanomas. Together, these data validate a role for p53inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.