The article reviews the advancements in treatment options for metastatic melanoma, particularly focusing on BRAF-mutant melanoma. Over the past five years, eight new therapeutic agents have been approved by the FDA, significantly improving patient outcomes. The standard treatment paradigm for BRAF-mutant disease has evolved from single-agent BRAF inhibition to combination therapy with BRAF and MEK inhibitors. Immunotherapy has also transitioned from cytokine-based treatments to antibody-mediated blockade of CTLA-4 and PD-1 immune checkpoints. These changes have led to a median overall survival of advanced-stage melanoma patients increasing from approximately 9 months before 2011 to at least 2 years. The article discusses the clinical trial data supporting these treatments, mechanisms of resistance, and biomarkers of response. It also explores the contrasting clinical benefits and limitations of these therapies, providing a rational approach to frontline treatment selection for BRAF-mutant melanoma patients. The genetic and immune landscapes of melanoma are discussed, highlighting the importance of understanding the molecular features of tumor-mediated immunosuppression. The article concludes by addressing the potential benefits and challenges of combining targeted agents and immunotherapies, as well as the need for further research to optimize treatment schedules and sequences.The article reviews the advancements in treatment options for metastatic melanoma, particularly focusing on BRAF-mutant melanoma. Over the past five years, eight new therapeutic agents have been approved by the FDA, significantly improving patient outcomes. The standard treatment paradigm for BRAF-mutant disease has evolved from single-agent BRAF inhibition to combination therapy with BRAF and MEK inhibitors. Immunotherapy has also transitioned from cytokine-based treatments to antibody-mediated blockade of CTLA-4 and PD-1 immune checkpoints. These changes have led to a median overall survival of advanced-stage melanoma patients increasing from approximately 9 months before 2011 to at least 2 years. The article discusses the clinical trial data supporting these treatments, mechanisms of resistance, and biomarkers of response. It also explores the contrasting clinical benefits and limitations of these therapies, providing a rational approach to frontline treatment selection for BRAF-mutant melanoma patients. The genetic and immune landscapes of melanoma are discussed, highlighting the importance of understanding the molecular features of tumor-mediated immunosuppression. The article concludes by addressing the potential benefits and challenges of combining targeted agents and immunotherapies, as well as the need for further research to optimize treatment schedules and sequences.