Understanding the genetic basis of the effects of aging on the decline in the immune response is an enormous undertaking. The most prominent age-related change in the immune system is thymic involution. This chapter will focus on the use of C57BL/6 J X DBA/2 J (BXD) recombinant inbred (RI) strains of mice to map genetic loci associated with age-related thymic involution in mice. Strategies to improve the power and precision in which complex traits such as the age-related decline in the immune response have been applied to the large set of BXD RI strains to detect quantitative trait loci (QTLs) that underlie thymic involution. More importantly, approaches have been developed to enable higher resolution mapping of these QTLs and, in some cases, may be adequate to carry out direct identification of candidate genes. It is likely that, given the complexity of the immune system development, the number of cells involved in an immune response, and especially the changes in the immune system with aging, multiple genetic loci and genes will contribute to the age-related changes in the immune response. This chapter outlines ongoing and general quantitative genetic linkage strategies that can be used for mapping and identification of the quantitative trait loci that may have a significant impact on age-related alteration of the immune system. © Humana Press Inc.