Mucosal melanoma presents a significant challenge for oncologists. Compared to cutaneous melanoma, mucosal melanoma has a far lower survival rate and is more difficult to treat. The lack of efficient therapies is at least partly due to our incomplete knowledge of what goes awry in mucosal pigment cells, the precursors of mucosal melanoma. Thus, a better understanding of which gene mutations cause the formation of mucosal melanoma and what molecular changes are elicited by such mutations is needed to develop improved therapies. Here, we propose to apply a novel approach termed ESC-GEMM to quickly develop transgenic mice to study mucosal melanoma development. Studying mucosal melanoma in ESC-GEMM mouse models offers several advantages. First, we will be able to study the development and evolution of mucosal melanoma within its natural environment. This is important to determine the effects of mutations on tumor growth and to assess the response of tumors to targeted therapies. Second, the ESC-GEMM approach is highly versatile and allows us to quickly adapt it to study many putative cancer genes in parallel. Third, the ESC-GEMM approach can generate experimental animals in as little as 2 months and thus dramatically accelerates the rate at which putative cancer genes can be analyzed. Fourth, the ESC-GEMM approach does not produce surplus mice that cannot be used for experiments and therefore significantly reduces the number of mice required for our studies. We will use the ESC-GEMM approach to study the function of the c-KIT gene, which is frequently overactive and/or mutated in human mucosal melanoma. We will test if c-KIT is able to promote the development of mucosal melanoma and compare tumor formation in the mucosa to that in normal skin. In addition, we will assess if mucosal melanomas with overexpressed normal or mutant c-KIT respond to an FDA-approved drug that inactivates c-KIT either alone or in combination with a drug that inhibits the MAPK signaling pathway downstream of c-KIT. Our ESC-GEMM mucosal melanoma model will not only help to better understand the role of c-KIT in mucosal melanoma development, but also be a powerful resource to interrogate the genetics of this melanoma subtype with the goal to design better treatment strategies.