CD4 is a critical component of the T cell receptor complex that recognizes peptides bound to MHC class II molecules. This can be observed at all stages of T cell development, activation, and function. CD4 has been termed a co-receptor to indicate that its most important activity is to bind the same peptide: self class II MHC complex as the T cell receptor and to transduce positive activating signals in conjunction with the T cell receptor. This behavior has been shown by several independent experimental systems: direct cross-linking of the T cell receptor to CD4, the inhibition of T cell activation by anti-CD4, the transfection of CD4 into CD4- T cells, and by the phenomenon of epitope interference, as described in this review. All of these approaches suggest that the participation of CD4 as a co-receptor in antigen: self class II MHC recognition potentiates activation by 100-fold. Given the complex nature of the ligand recognized by the T cell receptor, the co-receptor function of CD4 virtually eliminates the possibility of CD4 T cells recognizing peptides presented by class I MHC molecules, in keeping with many in vivo observations.