It has been shown that tumor suppressor genes (eg, p16) have pleiotropic effects during lifetime preventing the formation of cancer during early life but contributing to impairments in stem-cell function and organ maintenance during aging. Liu et al provide the first experimental evidence for lineage-specific pleiotropic effects of p16 in the aging immune system. B lineage–specific deletion of p16 leads to B cell–derived neoplasms in middle-aged mice without improving B lymphopoiesis at this age. In contrast, T lineage–specific deletion of p16 does not lead to tumorigenesis but significantly improves T lymphopoiesis and immune functions in aging mice. The data indicate that p16 does not contribute to tumor suppression in T-lymphoid cells but has an important tumor-suppressive role in B-lymphoid cells. In contrast, p16 contributes to impairments in T lymphopoiesis during aging but has no significant effects on B lymphopoiesis in middle-aged mice. Inhibitory effects of p16 on B lymphopoiesis at advanced age cannot be excluded. The data support a new concept indicating that lineage-specific gene-targeting (targeting of p16 in T-lymphoid lineage) could represent a therapeutic option to improve tissue maintenance during aging (T lymphopoiesis) without affecting gene expression and transformation in other compartments (B-lymphoid lineage).