To better understand the role of immunosurveillance in defense against brain tumors, the brain has been conceived as a “partially immunologically privileged” organ, meaning that antigens within the brain do not evoke an afferent response, probably because of effective maintenance of the blood-brain barrier (BBB) and subsequent influx of immune cells, lack of lymphatic drainage, and very low expression of major histocompatibility complex (MHC) molecules on most of the normal cells in the brain. During the earliest stage of oncogenesis, the BBB is intact and the immune system is normal. As the tumor grows, the accompanying histological or functional changes in vascular structures permit tumor antigens to leave the brain. As a result, the brain ceases to be an immunologically privileged organ. In response to the new antigenic stimulus, lymphocytes can proliferate and, most importantly, suppressor cells may be generated. The reason for the induction of suppressor activity remains unclear, but the result is a gradual loss of host immunocompetence. At this stage, the tumor becomes clinically evident, and the immune abnormalities are easily detected. Such suppressor cells may be generated by thymus-derived lymphocytes or macrophages. In addition, humoral suppression because of immune complexes may play a role in suppressor cell induction. It is postulated that in adult life the thymus maintains a regulatory population of T cells in peripheral lymphoid organs that suppress early T cell differentiation to cytotoxic effector cells and potentiate the development of immune memory. With regard to T cell-mediated immune responses, effector T cells of systemic origin have been shown to enter the brain in about 30% of glioma cases, for example, being manifested as perivascular accumulations of small lymphocytes. In contrast, natural killer (NK) cells are usually absent in brain tumors or present only in low amounts. However, the reason for the small number of NK cells in the brain is unclear, and there has been no definite evidence of NK cellmediated intracerebral immunosurveillance. Our recent experimental study (Yamasaki T et al. Experimental appraisal of the lack of antitumor natural killer cell-mediated immunosurveillance in response to lymphomas growing in the mouse brain. J Neurosurg 2003;98:599–606) based on a well-controlled, novel murine model provided the first data to suggest that the brain may lack an NK cell-mediated defense mechanism against tumors growing in the brain, representing another characteristic aspect of this immunologically privileged organ. It is accepted that NK cells are large, granular lymphocytes that mediate lysis of certain virally infected cells or tumor cells. The activity of NK cells is regulated by the expression of MHC Class I molecules on potential target cells. It has been proposed that a correlation exists between resistance to NK cell-mediated cytolysis and MHC Class I expression on tumor cells, although there are some exceptions. Thus, expression of MHC Class I molecules can protect target cells from NK cell cytotoxicity. This protection is mediated by inhibitory NK cell receptors that recognize MHC Class I molecules on target cells. Loss of MHC Class I expression can render cells sensitive to NK cell attack. Contact with sensitive target cells induces a series of signals in NK cells leading to target cell adhesion; polarization of surface receptors; and signaling molecules at the NK: target cell interface, followed by polarization and exocytosis of granules toward the target cell and the production of cytokines such as interferongamma. The interface that forms between NK and target cells is referred to as the “NK immunological synapse,” where adhesion molecules, other surface receptors, and cytoplasmic signaling molecules are recruited in an ordered manner.