Ag-experienced or memory T cells have increased reactivity to recall Ag, and can be distinguished from naive T cells by altered expression of surface markers such as CD44. Memory T cells have a high turnover rate, and CD8+ memory T cells proliferate upon viral infection, in the presence of IFN-αβ and/or IL-15. In this study, we extend these findings by showing that activated NKT cells and superantigen-activated T cells induce extensive bystander proliferation of both CD8+ and CD4+ memory T cells. Moreover, proliferation of memory T cells can be induced by an IFN-αβ-independent, but IFN-γ-or IL-12-dependent pathway. In these conditions of bystander activation, proliferating memory (CD44 high) T cells do not derive from activation of naive (CD44 low) T cells, but rather from bona fide memory CD44 high T cells. Together, these data demonstrate that distinct pathways can induce bystander proliferation of memory T cells.