Recent studies have shown that T cells are not just the latecomers in inflammation but might also play a key role in the early phase of this response. In this context, a number of T cell subsets including NKT cells, mucosal-associated invariant T cells and γ?δ T cells have been shown, together with classical innate immune cells, to contribute significantly to the development and establishment of acute and chronic inflammatory diseases. In this commentary we will focus our attention on a somewhat neglected class of T cells called CD3CD4CD8 double negative T cells and on their role in inflammation and autoimmunity. We will summarize the most recent views on their origin at the thymic and peripheral levels as well as their tissue localization in immune and non-lymphoid organs. We will then outline their potential pathogenic role in autoimmunity as well as their homeostatic role in suppressing excessive immune responses deleterious to the host. Finally, we will discuss the potential therapeutic benefits or disadvantages of targeting CD3CD4CD8 double negative T cells for the treatment of autoimmune disease. We hope that this overview will shed some light on the function of these immune cells and attract the interest of investigators aiming at the design of novel therapeutic approaches for the treatment of autoimmune and inflammatory conditions.