Part 2 of this review on cellular activation by the T-cell antigen receptor (TCR) will highlight how TCR signaling pathways are adapted to achieve specific biologic outcomes, including different states of T-cell differentiation and the induction of T-cell tolerance. We will also explore how treatment with altered peptide ligands affects TCR signaling to change T-cell differentiation or to induce an anergy state. These changes are accomplished through alteration of protein tyrosine kinase activity, the stoichiometry of phosphorylation of immunoreceptor tyrosine-based activation motifs, intracellular free ionized calcium flux, mitogen-activated protein kinase activity, and transcriptional activation of key cytokine promoters. The CTLA-4 plays an important role in the induction and maintenance of anergy. The second theme will highlight how altered TCR signal transduction, including changes in the compartmentalization of signaling components at the TCR synapse, contributes to decreased T-cell activation during immune senescence. Finally, we will illustrate how the molecular details of TCR activation can be used to modify the function of the immune system. This includes a description of the mechanism of action of altered peptide ligands, CTLA-4Ig, and pharmacologic inhibitors of mitogen-activated protein kinases, nuclear factor kappaB, and protein kinase C cascades.