Aging is associated with a myriad of changes including alterations in glucose metabolism, brain function, hormonal regulation, muscle homeostasis and the immune system. Aged dividuals, generally still defined as over 65 years old, differ from middle-aged or young donors in many features of the immune system. The major observation is that the elderly population is not able to cope with infections as well as younger adults and recovery generally takes longer. Moreover, some diseases first appear with advancing age and are likely associated with dysfunction of the immune system. Thus, Alzheimer's disease, atherosclerosis, type II diabetes and some autoimmune disorders are linked to changes in immune function. One major immune cell population implicated as being responsible for the initiation and chronicity of immune dysfunction leading to diseases or immunosuppression is the T-cell. Although many changes in B-cell and innate immune function in aging are associated with the appearance of disease, they are not as well studied and clearly demarcated as changes in the T-cell compartment. The adaptive immune system is coordinated by T-cells, the activation of which is required for the initiation, maintenance and termination of responses against pathogens. Changes in the expression and functions of the T-cell receptor (TCR) for antigen and its co-receptors are closely associated with immunosenescence. Certain similar changes have also been found in some other disease states, e.g., rheumatoid arthritis, systemic lupus erythematosus and cancer. In this chapter, we will summarize our knowledge about multichain immune recognition receptor signaling, mainly the TCR, in aging and autoimmune diseases.