Current treatments for metastatic melanoma are unsatisfactory, as very few patients achieve durable complete remissions. This project explores a novel concept for delivering immunotherapy, via nonmyeloablative allogeneic stem cell transplantation (Allo SCT). We hypothesize that the establishment of donor hematopoietic chimerism will induce a graft-versus-tumor (GVT) effect. A growing list of antigens have been identified on melanoma cells, which may elicit Class I or Class II T cell responses. The mechanism of GVT effect after Allo SCT is under intense scrutiny, and may involve T cell reactivity to minor histocompatibility antigens, as well as to tumor specific antigens. The Specific Aims of this proposal are: 1. Complete the first stage of a Phase II trial (FHCRC protocol 1462) of Allo SCT in patients with metastatic melanoma, to determine the clinical efficacy (as assessed by the objective response rate and survival) and toxicity (including graft-versus-host disease). Up to 15 patients with metastatic melanoma, who have achieved partial remission, minor remission, or stable disease after initial systemic therapy, will be treated. Eligible patients will receive low-dose total body irradiation (200cGy), and fludarabine, followed by infusion of peripheral blood stem cells from a HLA matched sibling donor, with post-transplant cyclosporine and mycophenylate mofetil. Subsequently, selected patients will receive donor lymphocytes to augment the GVT effect. 2. Evaluate immune responses, in patients undergoing Allo SCT, to known melanoma antigens, novel tumor-specific antigens, tissue-specific antigens, and minor histocompatibility antigens. The CD4+ and CD8+ T cell responses to defined peptides will be assessed by tetramer analysis, cytolytic effector function, and proliferative reactivity. Evaluation of the potential response, safety of Allo SCT, and elucidation of these T-cell responses will facilitate the development of future studies to manipulate GVT effect in patients with metastatic melanoma.