The review discusses the current state of melanoma therapy and the challenges of therapeutic resistance. Melanoma, the most aggressive and deadly form of skin cancer, has seen significant progress in treatment with targeted and immunotherapy. However, resistance to these therapies remains a major issue, with many patients experiencing tumor relapse. The review summarizes available therapeutic options and explores mechanisms of resistance. It highlights the role of BRAF and MEK inhibitors, immunotherapy agents like checkpoint inhibitors (e.g., ipilimumab, pembrolizumab, nivolumab), and other treatments such as radiation, chemotherapy, and oncolytic viruses. It also discusses the challenges in treating rare melanoma subtypes, including acral, mucosal, and uveal melanoma, and the need for more effective therapies. Additionally, the review explores the potential of riluzole, a drug approved for ALS, in treating mGluR1-driven melanoma by inhibiting glutamate export and inducing DNA damage, which may enhance immune responses. Riluzole shows promise in combination with immunotherapy, and preliminary clinical trials suggest its potential in melanoma treatment. The review emphasizes the importance of developing multifaceted therapies to address the diverse subtypes of melanoma and overcome resistance mechanisms.The review discusses the current state of melanoma therapy and the challenges of therapeutic resistance. Melanoma, the most aggressive and deadly form of skin cancer, has seen significant progress in treatment with targeted and immunotherapy. However, resistance to these therapies remains a major issue, with many patients experiencing tumor relapse. The review summarizes available therapeutic options and explores mechanisms of resistance. It highlights the role of BRAF and MEK inhibitors, immunotherapy agents like checkpoint inhibitors (e.g., ipilimumab, pembrolizumab, nivolumab), and other treatments such as radiation, chemotherapy, and oncolytic viruses. It also discusses the challenges in treating rare melanoma subtypes, including acral, mucosal, and uveal melanoma, and the need for more effective therapies. Additionally, the review explores the potential of riluzole, a drug approved for ALS, in treating mGluR1-driven melanoma by inhibiting glutamate export and inducing DNA damage, which may enhance immune responses. Riluzole shows promise in combination with immunotherapy, and preliminary clinical trials suggest its potential in melanoma treatment. The review emphasizes the importance of developing multifaceted therapies to address the diverse subtypes of melanoma and overcome resistance mechanisms.