A hypothesis is presented to explain the apparent difference in the radioresponsiveness of melanoma lesions whether they are located on the skin or in other parts of the body. The hypothesis states that the radiosensitivity of a cell may change when the cell adapts to live and grow in a different environment. The most important environmental factor that affects the radiosensitivity of cutaneous melanoma cells appears to be the partial pressure of oxygen in their immediate environment. By virtue of adapting to grow in an environment having a high partial pressure of oxygen, the melanoma cells located on the skin may have developed a better antioxidant defense mechanism than cells that metastasize to, and grow in, other parts of the body having lower partial pressures of oxygen such as lymph nodes, brain and viscera. Because some of the cell-damaging effects of both oxygen and ionizing radiation are mediated through a similar mechanism, the melanoma cells on the skin become cross-resistant to ionizing radiation because of their higher tolerance to oxygen toxicity.