Simple SummaryCutaneous melanoma is one of the deadliest forms of skin cancer. While advancements in systemic targeted therapies and immunotherapies have greatly improved melanoma survival in recent years, tumor resistance can limit the efficacy of these therapies. Targeting redox homeostasis in melanoma progression is a promising therapeutic approach, especially in cases of melanoma drug resistance. The role of oxidative stress in melanoma is paradoxical in that it promotes tumor initiation but prevents vertical growth and metastasis. As the disease progresses, melanoma employs adaptive mechanisms to decrease oxidative stress in the tumor environment. Thus, agents with antioxidant properties may have the greatest utility in chemoprevention whereas those with pro-oxidant properties may be better suited for treatment. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.AbstractCutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.