Telomere length is important in constraining the replicative potential of cells; cellular systems that are dependent on cell replenishment for renewal or on cell proliferation for functionality are highly sensitive to telomeric erosion. Cell replication invariably leads to telomere loss, which, in some cellular systems, is partially compensated for by telomerase activity. In addition to this typical telomere loss, several mechanisms of sporadic telomere loss exist. Heterogeneity in age-dependent telomere loss can be a consequence of increased cellular turnover during a lifetime, accelerated telomeric DNA damage, or defects in telomere repair. The immune system is a prime example of a highly dynamic cellular system, for which telomere maintenance is pivotal. Immune competence is strictly dependent on rapid expansions of clonal T- and B-cell populations, and telomere loss may contribute to defective immune responses in the elderly. Equally interestingly, accelerated T-cell aging combined with telomeric shortening may predispose for autoimmune responses and thereby explain the increased susceptibility for chronic inflammatory diseases in the elderly.