This is a competing renewal application for the Harvard SPORE in Skin Cancer, originally funded in October of 2001. This SPORE is based at Brigham and Women's Hospital and is part of the Skin Cancer Program of the Dana Farber Harvard Cancer Center. This proposal includes investigators from all major sites that participate in the DFHCC, as well as the Broad Institute of MIT. Seven translational research projects are proposed. Project 1 seeks to develop more precise and informative risk models for familial melanoma using genetic, genomic, and bioinformatic tools. Project 2 seeks to translate novel melanoma oncogenomic data into predictive and prognostic biomarkers and to identify novel pathways that are targets for drug development. Project 3 targets MITF, using the powerful genomic and bioinformatic resources of the Broad Institute to validate associated biomarkers and rationally identify novel inhibitors of this pathway. Project 4 seeks to explore the presence of cancer stem cells in melanoma, and to translate these findings to prediction, prognosis and therapy. Project 5 focuses on enhancing the modest clinical therapeutic effect of Braf inhibitors by discovering and targeting synergistic pathways with new compounds. Project 6 takes on the immunosuppressive milieu that thwarts immunotherapy in the advanced melanoma patients by targeting T regulatory cells while boosting antitumor immunity. Project 7 proposes targeted therapy for advanced CTCL, and seeks to develop therapeutic human antibodies to CCR4, a chemokine receptor faithfully expressed on these cells. These projects are supported by shared resources that include a Biostatistics Core, a Tissue and Pathology Core, and an Administration, Planning, and Evaluation Core. Successful Developmental Project and Career Development Award Programs constitute an important part of this SPORE, delivering new science and human talent to the translational skin cancer field. This proposed work is facilitated through substantial supplemental institutional commitments from each participating DFHCC hospital.