Oxidative stress limits distant metastasis by melanoma cells in vivo. Melanoma cells in the blood and visceral organs experience oxidative stress not observed in established subcutaneous tumors. Successfully metastasizing melanomas undergo reversible metabolic changes during metastasis that increase their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. Circulating cancer cells are commonly observed in the blood of patients and mice with various cancers. However, metastasis is a very inefficient process in which few disseminated cancer cells survive and even fewer proliferate. Some patients can have circulating cancer cells in their blood without evidence of metastasis or worse outcomes. Epithelial cells undergo cell death when they detach from extracellular matrix in culture as a result of reduced glucose uptake, ATP depletion, and oxidative stress. Oncogenic signaling can promote their survival by increasing glucose uptake and flux through the pentose phosphate pathway, which generates NADPH and regenerates glutathione, a buffer against oxidative stress. Glutathione is necessary for the initiation of some cancers and anti-oxidants can promote cancer initiation and progression. Cancer cells thus undergo genetic changes within primary tumours that increase their capacity to withstand oxidative stress, raising the question of whether additional adaptations are required during metastasis. Breast and lung cancer cell lines undergo metabolic changes during invasion in culture and metastasis in vivo that would be expected to reduce the generation of reactive oxygen species (ROS). Nonetheless, it is unknown whether ROS levels change in metastasizing cells in vivo or whether this limits distant metastasis. In fact, anti-oxidants inhibit the metastasis of some cancer cell lines, raising the possibility that ROS promotes metastasis in certain contexts. We addressed these issues by studying melanomas from multiple patients that were xenografted into NOD/SCID IL2R γ null (NSG) mice. Melanoma metastasis in this assay is predictive of clinical outcome in patients: stage III melanomas that metastasize efficiently in NSG mice go on to form distant metastases in patients, despite surgical resection, whereas melanomas that metastasize inefficiently in mice are usually cured by surgery in patients. Blood and viscera are hostile to metastasis. We obtained four efficiently and four inefficiently metastasizing melanomas from patients. All expressed melanoma markers. The efficiently metastasizing melanomas formed distant metastases in patients and in NSG mice after subcutaneous injection. The inefficiently metastasizing melanomas did not form distant metastases in patients or macOxidative stress limits distant metastasis by melanoma cells in vivo. Melanoma cells in the blood and visceral organs experience oxidative stress not observed in established subcutaneous tumors. Successfully metastasizing melanomas undergo reversible metabolic changes during metastasis that increase their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. Circulating cancer cells are commonly observed in the blood of patients and mice with various cancers. However, metastasis is a very inefficient process in which few disseminated cancer cells survive and even fewer proliferate. Some patients can have circulating cancer cells in their blood without evidence of metastasis or worse outcomes. Epithelial cells undergo cell death when they detach from extracellular matrix in culture as a result of reduced glucose uptake, ATP depletion, and oxidative stress. Oncogenic signaling can promote their survival by increasing glucose uptake and flux through the pentose phosphate pathway, which generates NADPH and regenerates glutathione, a buffer against oxidative stress. Glutathione is necessary for the initiation of some cancers and anti-oxidants can promote cancer initiation and progression. Cancer cells thus undergo genetic changes within primary tumours that increase their capacity to withstand oxidative stress, raising the question of whether additional adaptations are required during metastasis. Breast and lung cancer cell lines undergo metabolic changes during invasion in culture and metastasis in vivo that would be expected to reduce the generation of reactive oxygen species (ROS). Nonetheless, it is unknown whether ROS levels change in metastasizing cells in vivo or whether this limits distant metastasis. In fact, anti-oxidants inhibit the metastasis of some cancer cell lines, raising the possibility that ROS promotes metastasis in certain contexts. We addressed these issues by studying melanomas from multiple patients that were xenografted into NOD/SCID IL2R γ null (NSG) mice. Melanoma metastasis in this assay is predictive of clinical outcome in patients: stage III melanomas that metastasize efficiently in NSG mice go on to form distant metastases in patients, despite surgical resection, whereas melanomas that metastasize inefficiently in mice are usually cured by surgery in patients. Blood and viscera are hostile to metastasis. We obtained four efficiently and four inefficiently metastasizing melanomas from patients. All expressed melanoma markers. The efficiently metastasizing melanomas formed distant metastases in patients and in NSG mice after subcutaneous injection. The inefficiently metastasizing melanomas did not form distant metastases in patients or mac