We observed tail melanocytic hyperplasia in 3 out of 25 double mitfa- GFP-RAS transgenics at 24 dpf and one case of a head melanoma at 3 month of age. To understand the reasons of the difference between mitfa and kita driver lines in developing melanoma, we studied the cell types that express the oncogene under the control of the two driver lines. We found that in kita-GFP-RAS embryos and larvae other cell types not previously associated with the melanocytic lineage express the oncogene. None of these cell types display features of melanoblasts. However, there is a possibility that these cell types share the same lineage of melanocytes and that the kita-GFP line may provide insights on this. We then investigated if the differences between the two driver lines are due to different level of HRAS being expressed or maintained in melanocytes using western blot analysis, and found that in the mitfa-GFP-RAS line the levels of RAS expression are very low compared with those found in kita-GFP-RAS larvae and adults. This result suggest that the higher penetrance and earlier onset of melanoma in the kita-GFP-RAS line versus mitfa-GFP-RAS line could be due to the levels and persistence of oncogene expression, rather than to different cell specificity of the two promoters. Here we report on a genetic, inheritable zebrafish model of melanoma, which has a number of properties providing insights and tools for the study of melanoma biology and that shows features comparable to human melanoma. First, this model shows that expression of oncogenic HRAS can initiate and maintain melanoma formation without the need for inactivating mutations in tumor suppressors as reported for other models of melanoma. Second, the presence of a larval phenotype that is a direct precursor of the melanoma lesions that develop at later stages, allows rapid, easy to score and specific chemical screens aimed at finding compounds and drugs that may revert the hyper-pigmentation phenotype. Third, the model provides a rapid approach to gene manipulation specifically in the HRAS transformed cells, that could be exploited for large scale suppressor screens, through the use of UAS elements to drive expression of cDNA libraries, or for validation of drug target candidates. Fourth, the model allows to image BEZ235 cancer cells in vivo thanks to the expression of GFP. Genetic melanoma models which reproduce the human phenotype and provides a source of stageable cancer samples are strongly needed to test hypotheses on the mechanisms of Regorafenib purchase malignant transformation, identify melanoma initiating cells and study their features in order to devise way of eradicating them.