"Presently, there is little hope of cure for patients with metastatic melanoma. Greater insight into the molecular and cellular biology of melanoma and the immune response mounted against it is required to indicate new therapeutic approaches. We have created zebrafish models for analyzing melanoma initiation and progression. Using whole genome transcriptome profiling, we have identified a number of genes that are induced during malignant progression. Moreover, we have established an efficient method for assessing the ability of a given gene to promote melanoma progression in its natural setting. Having analysed the ontologies of our malignancy-associated gene set, we propose screening multiple exemplars from various functional categories, including classes of gene function not previously validated as therapeutic targets. We also propose using recombinant zinc-finger nucleases to delete candidate progression-inducing genes and determine their impact on melanoma progression. Experiments performed in cultured human melanoma cells will demonstrate conserved action. Recent collaborative work shows that melanoma cells, even when present as small clones, interact with neutrophils and macrophages, which appear to play both immunosurveillance and tumour-promoting roles. Likewise, CD4+ T cells play dual roles in shaping the immune response to melanoma. We have access to a macrophage-specific driver line and are in the process of developing a CD4+ T-cell specific driver line. Using these tools and other reagents, we propose to perform detailed analyses of neoplastic-melanocye–immune-cell interactions during malignant progression. Moreover, by driving expression of immunomodulatory factors, we shall follow the impact on progression of melanocyte neoplasms of manipulating the differentiation of these two leukocyte lineages. Pursuing these objectives will move us beyond the current boundaries of knowledge and lead to the discovery of novel therapeutic targets."