The study investigates the mechanisms behind the inefficiency of human melanoma cells in forming distant metastases. Melanomas were obtained from patients and transplanted into NSG mice to assess their metastatic potential. Efficient and inefficient metastasizers were identified based on their ability to form distant metastases in both patients and mice. Efficient metastasizers formed distant metastases in patients and mice, while inefficient metastasizers did not. Efficient metastasizers had higher frequencies of circulating melanoma cells in the blood and were more likely to form tumors after intravenous or intrasplenic transplantation. Metastatic cells experienced oxidative stress, with higher levels of ROS and lower GSH/GSSG ratios compared to subcutaneous tumors. Reversible metabolic changes, including increased NADPH production and folate pathway activity, were observed in metastatic cells. Anti-oxidants promoted distant metastasis, while folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited metastasis without affecting subcutaneous tumor growth. These findings suggest that oxidative stress limits distant metastasis by melanoma cells in vivo.The study investigates the mechanisms behind the inefficiency of human melanoma cells in forming distant metastases. Melanomas were obtained from patients and transplanted into NSG mice to assess their metastatic potential. Efficient and inefficient metastasizers were identified based on their ability to form distant metastases in both patients and mice. Efficient metastasizers formed distant metastases in patients and mice, while inefficient metastasizers did not. Efficient metastasizers had higher frequencies of circulating melanoma cells in the blood and were more likely to form tumors after intravenous or intrasplenic transplantation. Metastatic cells experienced oxidative stress, with higher levels of ROS and lower GSH/GSSG ratios compared to subcutaneous tumors. Reversible metabolic changes, including increased NADPH production and folate pathway activity, were observed in metastatic cells. Anti-oxidants promoted distant metastasis, while folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited metastasis without affecting subcutaneous tumor growth. These findings suggest that oxidative stress limits distant metastasis by melanoma cells in vivo.