T cells recognize their specific antigen when associated to the class I or class II molecules of the major histocompatibility complex (MHC). The T cell receptors, the effector molecules of specific antigen recognition are selected to have low affinity for self MHC molecules. Other molecules have been shown to play a major role in stabilizing the interaction between the TCR, self MHC and antigen. This review will focus on two of these molecules, namely CD4 and CD8. In contrast to other accessory molecules, the ligands of CD4 and CD8 are the same MHC molecules which are recognized by the T cell receptor. The structural analysis of the interaction between CD8, CD4 and their respective ligands, namely class I and class II molecules of the MHC, will be treated in this review. We will also discuss the possible differences which exist in the interaction of CD4 and CD8 with their respective ligands.