Melanoma is one of the few tumor types in which p53 is functionally repressed without extraneous mutations. With the number of kinase-based drug targets rapidly declining, p53 represents a relatively untapped resource for therapeutic intervention. Studies in other tumor types have demonstrated that reactivation of p53 is a viable strategy to initiate sustained tumor regression; combining p53 reactivation while inhibiting traditional genetic targets, such as mitogen-activated protein kinase/extracellular signal-related kinase kinase (MEK), holds therapeutic promise.