The use of heterologous species for clinical transplantation has attracted increasing interest in recent years due to the shortage of human donors, resulting in significant progress toward the understanding of the mechanisms leading to recognition and rejection of xenogeneic grafts. Analysis of the leukocyte infiltrates found in tissues undergoing delayed xenograft rejection (DXR) has led to the identification of natural killer (NK) lymphocytes as an important effector cell subset. This paper focuses on the role of NK cells in xenogeneic graft rejection, on the biology of NK cells, and on NK-cell receptors in particular. NK cells contribute to the natural host defense mechanisms, both by exerting cytotoxicity on certain virally infected or tumor cells and by releasing cytokines that promote an inflammatory response, such as γ-interferon (IFN), tumor necrosis factor (TNF), granulocyte/macrophage-colony stimulating factor, and macrophage colony-stimulating factor. During NK-cell ontogeny, the CD34 surface antigen is lost and cells acquire the expression of membrane markers characteristic of mature NK cells (CD2, CD 16, CD56). Chimerism induced by donor-specific bone marrow transplantation has been shown to produce alio- and xenotolerance, even across a discordant barrier, with evidence of NK as well as T- and B-cell tolerance. However, it seems likely that more than one of the approaches briefly outlined above might be eventually necessary to efficiently prevent NK-cell-mediated xenograft damage.