The expression of CD4 and CD8αβ 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 α-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 CD8αβ heterodimer (CD4^hiCD8^hi), has been identified in autoimmune and chronic inflammatory disorders. While no definitive proof exists, it could be speculated that CD4^hiCD8^hi T cells may be endowed with auto-reactivity due to faulty thymic selection.