The epidermis of normal mouse skin incorporates a newly-recognized population of dendritic cells which express relatively large amounts of the cell surface glycoprotein, Thy-1 antigen. These cells, termed Thy-1+dEC, are distinct from both epidermal Langerhans cells (LC) and melanocytes, and they populate cutaneous sites in surface densities which range to as high as 580 cells/mm2, approximately two-thirds that of LC. Studies of lethally irradiated mice which were reconstituted with semiallogeneic bone marrow cells and mice which received grafts of semiallogeneic skin have demonstrated that some, if not all, Thy-1+dEC are of bone marrow origin, and that they are capable of migrating into epidermis from a vascular source. Thy-1+dEC expressed both asialo GM1 and a cell surface determinant recognized by the monoclonal antibody 20-10-5S, further suggesting their functions will be included among those normally ascribed to lymphoreticular cells. Isolation of epidermal cells with the Fluorescence Activated Cell Sorter (FACS) was successful in producing relatively pure populations of Thy-1+dEC and LC. Such technological advances as this should facilitate testing several hypotheses concerning the ultimate function of these cells, including the possibilities that they are antigen-presenting cells which selectively activate down-regulating signals, T lymphocytes, natural killer (NK) cells, or natural suppressor (NS) cells.