Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. NT cells are mainly composed of alphabeta and gammadelta T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can see and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the alphabeta TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and alkylamines induce constitutive response of Vgamma9Vdelta2 T cells. The stimulation of Vgamma9Vdelta2 T cells with phosphocarbohydrates induces the production of cytokines (IFNgamma and TNFalpha) and the release of chemokines with suppressive activity on HIV replication. In addition, stimulated Vgamma9Vdelta2 T cells exert a cytolytic activity against HIV-infected targets. In HIV-infected patients, a quantitative and qualitative alteration is observed early during the infection. Vgamma9Vdelta2 T cells are deleted and the remaining gammadelta cells are anergic. Th1 cytokines (IL-12 and IL-15) positively regulate cytokine production by Vgamma9Vdelta2 T cells but they are inefficient in restoring normal functions in patients' gammadelta T cells. Interestingly, partial restoration of the immune system under highly active antiretroviral therapies (HAART) is associated to the recovery of functional Vgamma9Vdelta2 T cells. A large panel of phosphocarbohydrates able to selectively stimulate Vgamma9Vdelta2 T cells is currently available, and preliminary experiments in monkeys suggest their in vivo efficacy in helping to control SIV replication. These observations prompt the question of new immune intervention involving molecules that stimulate NT cells.