The amazing initial response rate (87-90%)1,2 to targeted therapies in BRAF mutant melanoma patients is undermined by the development of resistance and disease progression that occurs in ~70% of patients1. Strategies to prolong or maintain these initial responses would be a clear game-changer in the treatment of melanoma. Several recent retrospective studies have shown increased overall survival in obese (BMI:>30) and overweight (BMI:25-30) melanoma patients treated with either immune- or targeted-therapy but not chemotherapy3-6. This is surprising given the abundance of evidence linking obesity with increased risk of cancer. Using our novel syngeneic mouse model 7, we are able to replicate the human data showing that a high-fat diet increased the efficacy of BRAF/MEK inhibitors. Surprisingly, in immune-compromised Rag mice that are deficient in lymphoid cells but still have functional macrophages this increase in efficacy is also apparent, but importantly to a lesser degree. Furthermore, in NSG mice that lack macrophages, B, T, and NK cells, there is still a fat-induced increase in efficacy, clearly demonstrating a non-immune component to the phenotype. Thus, we have a model system to address the mechanism(s) underpinning the association of body fat with improved outcomes to targeted therapy in melanoma. By understanding the biological basis for this association, we will further understand how to enhance these initial responses and design rational novel therapeutic strategies (targeted, hormonal, immune, metabolic, dietary) that will improve the outcomes for patients and importantly, avoid the adverse health effects associated with being overweight.