Skin cancer is the most common cancer worldwide, with melanoma being the most aggressive and deadly form. Recent decades have seen significant advancements in targeted therapy and immunotherapy, significantly improving survival rates for melanoma patients. However, many patients do not respond to these treatments, and most experience tumor relapse after initial response. This review summarizes the current therapeutic options for melanoma and the mechanisms of resistance to these therapies. It highlights the need for continuous efforts to develop new treatments and understand the underlying mechanisms of resistance. The review also discusses the potential of multifaceted therapeutics to treat various subtypes of melanoma and other cancers, particularly focusing on the role of glutamate signaling and the use of riluzole, a drug approved for Amyotrophic Lateral Sclerosis (ALS), in treating mGluR1-driven melanoma. Riluzole has shown promise in reducing extracellular glutamate levels, inhibiting cell proliferation, and increasing apoptosis in mGluR1-positive melanoma cells. Combining riluzole with immunotherapy agents, such as anti-PD-1 inhibitors, may further enhance its therapeutic effects. The review also explores the broader therapeutic potential of riluzole in other cancers, including breast, pancreatic, prostate, and brain cancers, where it has demonstrated efficacy through various mechanisms.Skin cancer is the most common cancer worldwide, with melanoma being the most aggressive and deadly form. Recent decades have seen significant advancements in targeted therapy and immunotherapy, significantly improving survival rates for melanoma patients. However, many patients do not respond to these treatments, and most experience tumor relapse after initial response. This review summarizes the current therapeutic options for melanoma and the mechanisms of resistance to these therapies. It highlights the need for continuous efforts to develop new treatments and understand the underlying mechanisms of resistance. The review also discusses the potential of multifaceted therapeutics to treat various subtypes of melanoma and other cancers, particularly focusing on the role of glutamate signaling and the use of riluzole, a drug approved for Amyotrophic Lateral Sclerosis (ALS), in treating mGluR1-driven melanoma. Riluzole has shown promise in reducing extracellular glutamate levels, inhibiting cell proliferation, and increasing apoptosis in mGluR1-positive melanoma cells. Combining riluzole with immunotherapy agents, such as anti-PD-1 inhibitors, may further enhance its therapeutic effects. The review also explores the broader therapeutic potential of riluzole in other cancers, including breast, pancreatic, prostate, and brain cancers, where it has demonstrated efficacy through various mechanisms.