Immune checkpoint inhibitors (ICIs) have revolutionized treatment of metastatic cutaneous melanoma causing durable responses and cure in an unprecedented fraction of patients. However, half of all patients still progress and virtually all patients with metastatic uveal melanoma. In this presentation my lab's approaches to treat therapy-resistant melanoma of the skin and eye is presented. The work is translational and has resulted in enhanced understanding of genetics of melanoma, development of novel patient-derived xenograft models and initiation of several trials, especially for patients with metastatic uveal melanoma. Updates of current laboratory studies on genetics, cell therapy as well as trial activities will be presented. The presentation should interest both preclinical scientists and clinicians.