The study investigates the frequency of tumorigenic human cancer cells in melanoma, a type of skin cancer. Traditional studies using NOD/SCID mice, which are highly immunocompromised, have suggested that only a small fraction of human cancer cells (0.1–0.0001%) are tumorigenic. However, this study demonstrates that modified xenotransplantation assays can significantly increase the detection of tumorigenic melanoma cells. By using more immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg−/−) mice and co-injecting cells with Matrigel, the frequency of tumorigenic melanoma cells increased by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients formed tumors under these conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumors. These results indicate that tumorigenic cells are common in some human cancers, contrary to the traditional view that they are rare. The study also shows that the tumorigenic potential of melanoma cells is not phenotypically distinguishable from non-tumorigenic cells, suggesting that other factors may be involved in determining tumorigenicity. The findings have implications for cancer therapy, as targeting the small minority of cancer stem cells may not be effective if tumorigenic cells are more common than previously thought.The study investigates the frequency of tumorigenic human cancer cells in melanoma, a type of skin cancer. Traditional studies using NOD/SCID mice, which are highly immunocompromised, have suggested that only a small fraction of human cancer cells (0.1–0.0001%) are tumorigenic. However, this study demonstrates that modified xenotransplantation assays can significantly increase the detection of tumorigenic melanoma cells. By using more immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg−/−) mice and co-injecting cells with Matrigel, the frequency of tumorigenic melanoma cells increased by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients formed tumors under these conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumors. These results indicate that tumorigenic cells are common in some human cancers, contrary to the traditional view that they are rare. The study also shows that the tumorigenic potential of melanoma cells is not phenotypically distinguishable from non-tumorigenic cells, suggesting that other factors may be involved in determining tumorigenicity. The findings have implications for cancer therapy, as targeting the small minority of cancer stem cells may not be effective if tumorigenic cells are more common than previously thought.