The co-receptors CD4 and CD8 are important in the activation of T cells primarily because of their ability to interact with the proteins of the MHC enhancing recognition of the MHC-peptide complex by the T cell receptor (TCR). An antigen-presenting cell presents a small number of antigenic peptides on its MHC molecules, in the presence of a much larger number of endogenous, mostly nonstimulatory, peptides. Recent work has demonstrated that these endogenous MHC-peptide complexes have an important role in modulating the sensitivity of the TCR. But the role of the endogenous nonstimulatory MHC-peptide complexes differs in MHC class I and class II-restricted T cells. This chapter discusses the data on the role of CD4 or CD8 co-receptors in T cell activation at the immunological synapse, and the role of non stimulatory MHC-peptide complexes in aiding antigen recognition.