Coordinated migratory events are required for the development of effective and regulated immunity. Naïve T lymphocytes are programmed to recirculate predominantly in secondary lymphoid tissue by non-specific stimuli. In contrast, primed T cells must identify specific sites of antigen location in non-lymphoid tissue to exert targeted effector responses. Following priming, T cells acquire the ability to establish molecular interactions mediated by tissue-selective integrins and chemokine receptors (homing receptors) that allow their access to specific organs, such as the skin and the gut. Recent studies have shown that an additional level of specificity is provided by the induction of specific T cell migration into the tissue following recognition of antigen displayed by the endothelium. In addition, co-stimulatory signals (such as those induced by CD28 and CTLA-4 molecules) have been shown not only to regulate T cell activation and differentiation, but also to orchestrate the anatomy of the ensuing T cell response. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.