Memory T cells are essential for generating secondary immune responses and so provide long-lived protection from pathogens. The mechanisms that regulate the differentiation and survival of memory T cells are largely unknown. Transgenic mice in which NF-kappaB activity is inhibited by the expression of a dominant-negative form of IkappaB-alpha (mIkappaB-alpha mice) have drastically diminished numbers of CD8(+) memory-phenotype cells. The development of activated mIkappaB-alpha CD8 cells into memory-phenotype CD8 cells was severely impaired after adoptive transfer to lymphopenic hosts. Our findings demonstrate a critical role for NF-kappaB transcription factors in determining the number of memory-phenotype CD8 cells.