This paper shows that treatment of melanoma cells with methotrexate (an inhibitor of dihydrofolate reductase (DHFR)) induces the expression of microphthalmia-associated transcription factor (MITF). MITF induces melanocyte differentiation by inducing the transcription of genes, such as tyrosinase (TYR), and inhibits invasive growth. Expression of TYR enables the activation of a prodrug, 3-O-(3,4,5-trimethoxybenzoyl)-(–)-epicatechin (TMECG), which also inhibits DHFR. Combined treatment of melanoma cells with methotrexate and TMECG depletes thymidine pools and induces DNA damage and apoptosis in vivo.