In contrast to naïve CD4 + T cells, memory CD4 + T cells rapidly express high levels of effector cytokines in response to antigen stimulation. The molecular mechanism for this specific behavior is not well understood. The nuclear factor of activated T cells (NFAT) family of transcription factors plays an important role in the transcription of many cytokine genes. Here we show that memory CD4 + T cells rapidly induce NFAT-mediated transcription upon T cell receptor ligation whereas NFAT activation in naïve CD4 + T cells requires longer periods of stimulation. The difference in kinetics correlates with the low levels of NFATc1 and NFATc2 proteins present in naïve CD4 + T cells and their high levels in memory CD4 + T cells. Accordingly, IL-2 expression requires NFAT activation only in memory CD4 + T cells whereas it is NFAT-independent in naïve CD4 + T cells. Thus, the accumulation of NFATc1 and NFATc2 in memory CD4 + T cells represents a previously uncharacterized regulatory mechanism for the induction of early gene expression after antigen stimulation.