Melanoma is noted for its alarming increase in incidence, especially amongst the young, aggressive clinical behavior and propensity for lethal metastasis, illustrating an urgent need for new treatment strategies for this disease. However, despite the bleak clinical and epidemiological picture, genetic analysis has uncovered key driver oncogenes in melanoma such as mutationally activated BRAF. Importantly, when mutationally activated BRAF is pharmacologically inhibited with vemurafenib, BRAF mutated melanoma patients, even those with widely disseminated, metastatic disease, have enjoyed dramatic tumor regression coupled with significant health improvement. However, since the durability of such responses is limited by the emergence of lethal drug resistant disease, there is a strong emphasis on developing combination therapies to increase the durability of patient response. Another frequent alteration in melanoma is silencing of INK4A, a key regulator of the cell division cycle. INK4A silencing leads to unrestrained activity of two key enzymes, CDK4 and CDK6, which are inhibited by the Pfizer drug PD332991. Here we propose to use genetically engineered mouse (GEM) models of BRAF/INK4A mutated melanoma, which accurately model the human disease, in conjunction with human melanoma cell lines to test the ability of PD332991, either alone or in combination with vemurafenib, to inhibit melanoma growth. Studies proposed here offer the long-term prospect of evidence-based, effective, durable and comparatively less toxic chemotherapy for patients with advanced melanoma based on a molecular understanding of how signal transduction pathways and the machinery of the cell division cycle contribute to the aberrant biology and biochemistry of the melanoma cell.