The entry of T-lymphocytes into the parenchyma of the central nervous system is a critical early feature in the pathogenesis of many experimental and spontaneously occurring immune-mediated illnesses. The physiological mechanisms controlling this entry have not been elucidated. This study reports that T-cell entry into the rat CNS appears to be primarily dependent upon the activation state of the lymphocytes; T-lymphoblasts enter the CNS (and all other tissues examined) in an apparently random manner while T cells not in blast phase are excluded. Antigen specificity, MHC compatibility, T-cell phenotype, and Tcell receptor gene usage do not appear related to the ability of cells to enter. This study demonstrates that when T-lymphoblasts are introduced into the circulation they rapidly appear in the CNS tissue. Their concentration in the CNS reaches a peak between 9 and 12 hr, and lymphocytes which have entered, exit within 1 to 2 days. Cells capable of reacting with a CNS antigen remain in the tissue or cyclically reenter to initiate inflammation if they are able to recognize their antigen in the correct MHC context. This observation also appears to pertain to the entry of activated T cells into many other tissues, although their concentrations in these non-CNS sites was not quantita tied.