The particular T cell subsets involved in the rejection of tumor allografts were examined in mice using two different approaches. In the first, EL4 lymphoma cells or B16 melanoma cells were given to ATXBM-CBA/H mice which had been reconstituted with either naive or sensitized T cells selectively depleted with either Ly-1 or Ly-2 monoclonal antibodies. In mice receiving nonsensitized T cells, Ly-123 cells and to a lesser extent Ly-1 cells were involved in the rejection of both tumors: Ly-23 cells played no role in this rejection. By contrast, in mice receiving sensitized cells, rejection was mediated by Ly-1 cells and not by Ly-123 or Ly-23 cells. In a second approach, sensitized cells were mixed with the tumor cells prior to injection into mice (the Winn neutralization assay). In this case, Ly-123 cells were the prime mediators of graft rejection. We conclude that both Ly-1 and Ly-123 cells can act as mediators of graft rejection. Ly-1-sensitized cells probably act as in a delayed-type hypersensitivity (DTH) response where few lymphocytes can lead to the rejection of many cells. In addition, Ly-123 cells can act as killer T cells but large numbers and the close apposition with the target cells are required. Our results also demonstrate a requirement for Ly-123 precursor cells in nonsensitized mice, probably acting as precursors for both types of effector cell.