Melanoma has now become the subject of targeted therapies, based upon the high prevalence of B-raf mutations in melanoma. However, while initial responses to B-raf inhibitors are impressive, resistance is extremely common, suggesting that melanoma is not addicted to B-raf. In their report, Syed et al. demonstrate that fisetin, a natural product without well established mechanisms, has activity against melanoma. Their report suggests that "nontargeted therapies" need to become part of our armamentarium against melanoma, given that targeted therapies do not target all of the pathways required for melanoma growth.