Cutaneous melanoma is the most aggressive type of skin cancer and its global incidence rates are significantly increasing. Many recent therapeutic advances have been developed for the treatment of unresectable melanoma and have significantly improved survival in melanoma patients. Immune checkpoint inhibitors and small molecule targeted therapies that decrease tumour cell proliferation and induce cell death through targeting BRAF and its downstream molecule MEK are currently standard of care treatment for melanoma patients. Despite all the advancements achieved using immunotherapy and/or combining molecular targeted therapies, unfortunately, most patients develop resistance after the amazing initial response to these therapies. Due to the multitude of resistance mechanisms, strategies to delay/or confine the development of resistance to therapy would be a clear game changer in the treatment of melanoma and provide a more universal and effective treatment. Interestingly, obesity has been shown to significantly improve responses to both targeted and immunotherapy in male melanoma patients. Considering the metabolic abnormalities arising because of body fat gain, improved BRAF/MEK targeted therapy efficacy following obesity is counterintuitive. The underlying mechanisms on how obesity improves the efficacy of MAPK pathway targeted therapy in melanoma patients is unknown. Recently from our lab we are able to replicate the human data showing a highly significant increase in efficacy of BRAF/MEK inhibition in mice with excess adipose tissue as a result of a high-fat diet. Finding the biological basis for this association will help to further understand how to improve the drug response without the adverse health effects related to being overweight. Finally, such information will help to develop novel therapeutic strategies that will improve the targeted therapy outcomes for melanoma patients.