Conventional virgin T cells efficiently and homogeneously recirculate through all secondary lymphoid tissues, but not “extralymphoid” effector sites. In contrast, memory/effector populations are composed of distinct subsets with differential, often tissue-selective, migratory capability to both secondary lymphoid tissues and effector sites. In keeping with these observations, CD45RAhigh/ROlow virgin T cells in human peripheral blood uniformly express the peripheral lymph node (PLN) homing receptor (HR) L-selectin, and lack the skin-selective HR CLA, whereas among the CD45RAlow/ROhigh “memory/effector” population, differential expression of these HR yields three predominant subsets: L-selectin+/CLA+, L-selectin+CLA−, L-selectin+CLA−. Although these subsets are of approximately equal size in the peripheral blood, the vast majority of T cells obtained from cutaneous chronic inflammatory sites display the L-selectin+/CLA+ phenotype. To investigate the mechanisms responsible for the generation of these memory/effector T-cell subsets, we developed a multiparameter flow cytometric technique that defines a common pathway of post-thymic T-cell differentiation in secondary lymphoid tissues: the virgin to memory/effector transition. Our analyses indicate that these HR are differentially regulated during the virgin to memory/effector transition in a tissue-specific fashion. The great majority of memory/effector T cells produced in PLN retain high levels of L-selectin expression, and 50 to 60% upregulate CLA. In contrast, memory/effector T cells produced in appendix and tonsil are generally L-selectinlow, and CLA is upregulated on less than 10% of newly formed memory/effector T cells in appendix and on about 30 to 35% of such cells in tonsil. Taken together, these findings support the hypothesis that local microenvironments within particular secondary lymphoid tissues influence HR expression at the time of the virgin to memory/effector transition, and thereby contribute to the formation of CD45RAlow/ROhigh memory/effector T-cell populations with tissue-selective homing behavior.