OBJECTIVE This review summarizes recent knowledge on the role of receptor tyrosine kinases, particularly erythropoietin-producing hepatocyte kinases (Ephs), in T-cell function and development. RESULTS Erythropoietin-producing hepatocyte kinase function and signaling in the immune system have been recently investigated. Cross-linking some Ephs results in T-cell costimulation and reduces the response threshold of T-cell receptor activation. In vivo, T-cell-mediated responses are compromised in EphB6-/- mice. Some Ephs are shown to control T-cell migration and adhesion, as well as the integrity of lymphoid organ structure. CONCLUSIONS Ephs are the largest family of receptor tyrosine kinases. Some Ephs are expressed in the lymphoid organs. Ephrins, ligands of Ephs, are also cell surface molecules. Cross-linking of certain Ephs facilitates T-cell activation and proliferation. Under physiologic conditions, such cross-linking by ephrins likely occurs in lymphoid organs, where ephrins on T cells interact with ephrins on the surface of neighboring fraternal T cells or antigen-presenting cells; this may explain why T-cell responses are more effectively initiated in the lymphoid organs. Certain Ephs are also critical for lymphocyte adhesion and migration and for proper lymphoid organ structure. Ephs and ephrins are highly redundant and their interactions promiscuous, suggesting pivotal roles of these molecules in biology. Conversely, such redundancy represents a major challenge to further dissection of the function of individual Ephs. Multiple tissue-specific gene null mutations on Ephs or ephrins will likely reveal more interesting immune-related phenotypes.