Melanoma occurs when pigment cells, melanocytes, acquire oncogenic mutations and they start to divide uncontrollably. If the cells spread and form metastases then melanoma is potentially a deadly disease. The last years have seen a revolution in the treatment of metastatic skin melanoma with the approval of both targeted therapy (BRAF/MEK inhibitors) and immunotherapies (immune checkpoint inhibitors, ICI). Unfortunately, half of all patients’ melanoma are resistant, or acquire resistance, to these novel therapies, resulting in death of around 1500 Australians a year. This is especially true for melanoma of the eye, uveal melanoma (UM), where basically all with metastases succumb to their disease. Here, translational and clinical research of melanoma utilizing knowledge from the field of genetics, epigenetics and immunology to devise new immunotherapy strategies will be presented. Focus will be on the use of animal models (PDXs) that can be used as personalized research tools or to test novel immunotherapies from bench to bedside. Furthermore our recent trial data of immunotherapy for patients with uveal melanoma trial will be discussed.