Naive and effector/memory T cells have distinct repertoires of trafficking ligands and receptors that restrict their ability to interact with specialized microvessels in different anatomical compartments and, consequently, have distinct patterns of migration. Antigen-experienced lymphocytes can be further subdivided into different subsets based on their expression of characteristic sets of trafficking receptors that favor their accumulation in certain target organs, including the skin and gut. Here, we summarize recent advances that have broadened our understanding of the cellular and molecular events that induce the generation of tissue-specific effector/memory T cells and discuss how these mechanisms could be harnessed for the therapeutic manipulation of T-cell-dependent pathologies.