The expression of CD4 and CD8alphabeta co-receptors on mature T cells is generally considered to be mutually exclusive and reflects subset-related, specific functions (helper vs. cytolytic) and differences in major histocompatibility complex-restriction for antigen recognition. However, double positive (DP) T cells expressing both CD4 and CD8 have been described in several pathological conditions as well as in normal individuals. DP T cells represent a heterogeneous population. Strong evidence indicates that in vivo terminally differentiated effector CD4 may acquire the alpha-chain of CD8. Reciprocally, in vitro activation of CD8+ T cells results in the expression of low levels of CD4 that may mediate HIV entry and responses to chemotactic cytokines. Particularly intriguing, a subset of DP T cells expressing high levels of both CD4 and CD8alphabeta heterodimer (CD4(hi)CD8(hi)), has been identified in autoimmune and chronic inflammatory disorders. While no definitive proof exists, it could be speculated that CD4(hi)CD8(hi) T cells may be endowed with auto-reactivity due to faulty thymic selection.