Increasing generations of the telomerase knockout mouse, Terc-/-, show severe telomere dysfunction characterized by critically short telomeres and end-to-end chromosomal fusions. These mice also suffer from various age-related diseases affecting highly proliferative tissues. Among these pathologies are a reduced proliferative capacity of B and T cells, as well as a reduction of germinal center reactivity upon immunization. Both immune system defects are landmarks of immunosenescence. The study of the telomerase-deficient mouse model supports the notion that telomere shortening with age contributes to immunological dysfunction in the elderly.