Like other tumors, advanced melanomas include a mix of cells with different genetics and behaviors. For example, some melanoma cells don't divide rapidly. These differences can help some melanoma cells evade targeted therapies, making it impossible to kill off the tumor. Now, researchers report a new combination treatment that sidesteps resistance: methotrexate, a conventional chemotherapy drug, and TMECG, a new toxic molecule made by the researchers. Methotrexate pushes melanoma cells to divide and to make a protein called tyrosinase. The new toxic molecule TMECG is activated by tyrosinase, and so then targets the melanoma cells. Besides being specific to melanomas, this new combination treatment works on tumors that have resisted all other therapies.