The article discusses the treatment of advanced-stage melanoma, focusing on targeted agents and immunotherapies. Over the past five years, significant progress has been made in treatment options for patients with metastatic melanoma, particularly BRAF-mutant melanoma, with the FDA approving eight new therapeutic agents. The standard-of-care treatment for BRAF-mutant disease has shifted from single-agent BRAF inhibition to combination therapy with BRAF and MEK inhibitors. Immunotherapy has also evolved, transitioning from cytokine-based treatment to antibody-mediated blockade of immune checkpoints such as CTLA-4 and PD-1. These changes have significantly improved patient outcomes, with median overall survival increasing from approximately 9 months before 2011 to at least 2 years. The article reviews clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. It discusses mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies, as well as the clinical benefits and limitations of these therapies. The treatment landscape for advanced-stage, unresectable or metastatic melanoma has shifted dramatically, with eight therapeutic agents approved by the FDA for melanoma treatment. These include BRAF and MEK inhibitors, immunotherapeutic antibodies, and the modified oncolytic herpes virus T-VEC. The article also discusses the genetic and immune landscape of melanoma, highlighting the role of BRAF and MEK mutations in melanoma development. It explores the importance of immune recognition in melanoma, noting that robust lymphocyte infiltration into primary melanomas is associated with a reduced risk of metastasis. The article reviews clinical trial evidence for BRAF-targeted and immunotherapy approaches, showing substantial improvements in overall survival for patients with advanced-stage melanoma. The article discusses the combination of BRAF and MEK inhibitors, which has become the standard-of-care treatment for BRAF-mutant melanoma. It also explores the use of immune-checkpoint inhibitors, such as ipilimumab and nivolumab, which have shown significant efficacy in treating melanoma. The article highlights the importance of understanding resistance mechanisms and biomarkers of response to these therapies. It also discusses the potential benefits of combining targeted and immunotherapy approaches, as well as the need for further research to optimize treatment strategies for individual patients.The article discusses the treatment of advanced-stage melanoma, focusing on targeted agents and immunotherapies. Over the past five years, significant progress has been made in treatment options for patients with metastatic melanoma, particularly BRAF-mutant melanoma, with the FDA approving eight new therapeutic agents. The standard-of-care treatment for BRAF-mutant disease has shifted from single-agent BRAF inhibition to combination therapy with BRAF and MEK inhibitors. Immunotherapy has also evolved, transitioning from cytokine-based treatment to antibody-mediated blockade of immune checkpoints such as CTLA-4 and PD-1. These changes have significantly improved patient outcomes, with median overall survival increasing from approximately 9 months before 2011 to at least 2 years. The article reviews clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. It discusses mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies, as well as the clinical benefits and limitations of these therapies. The treatment landscape for advanced-stage, unresectable or metastatic melanoma has shifted dramatically, with eight therapeutic agents approved by the FDA for melanoma treatment. These include BRAF and MEK inhibitors, immunotherapeutic antibodies, and the modified oncolytic herpes virus T-VEC. The article also discusses the genetic and immune landscape of melanoma, highlighting the role of BRAF and MEK mutations in melanoma development. It explores the importance of immune recognition in melanoma, noting that robust lymphocyte infiltration into primary melanomas is associated with a reduced risk of metastasis. The article reviews clinical trial evidence for BRAF-targeted and immunotherapy approaches, showing substantial improvements in overall survival for patients with advanced-stage melanoma. The article discusses the combination of BRAF and MEK inhibitors, which has become the standard-of-care treatment for BRAF-mutant melanoma. It also explores the use of immune-checkpoint inhibitors, such as ipilimumab and nivolumab, which have shown significant efficacy in treating melanoma. The article highlights the importance of understanding resistance mechanisms and biomarkers of response to these therapies. It also discusses the potential benefits of combining targeted and immunotherapy approaches, as well as the need for further research to optimize treatment strategies for individual patients.