Secondary antibody responses are characterized by the rapid kinetics of the responding cells, including the production of larger amounts of serum Ig compared with the primary response. Memory B cells, which are responsible for this phenomenon, undergo greater proliferation and differentiation into Ig-secreting plasma cells than naïve B cells. We have found that memory cells rapidly enter cell division, irrespective of extrinsic stimuli. Microarray analysis of human splenic B cells revealed that naïve cells express higher levels than memory B cells of Krüppel-like factor (KLF) 4, KLF9, and promyelocytic leukemia zinc finger (PLZF), transcription factors important in maintaining cellular quiescence. These genes were down-regulated after activation through CD40 and the B cell receptor. Enforced expression of KLF4, KLF9, and PLZF in memory B cells delayed their entry into division and reduced the number of proliferating cells, such that the behavior of transfected memory cells resembled that of naïve B cells. Thus, the accelerated response of memory B cells correlates with reduced expression of KLF4, KLF9, and PLZF and the subsequent regulatory effects they exert on the cell cycle.