CD4⁺ T cell priming under T helper type I (T_H1) or T_H2 conditions gives rise to polarized cytokine gene expression. We found that in these conditions human naive T cells acquired stable histone hyperacetylation at either the Ifng or Il4 promoter. Effector memory T cells showed polarized cytokine gene acetylation patterns in vivo, whereas central memory T cells had hypoacetylated cytokine genes but acquired polarized acetylation and expression after appropriate stimulation. However, hypoacetylation of the nonexpressed cytokine gene did not lead to irreversible silencing because most T_H1 and T_H2 cells acetylated and expressed the alternative gene when stimulated under opposite T_H conditions. Such cytokine flexibility was absent in a subset of T_H2 cells that failed to up-regulate T-bet and to express interferon-γ when stimulated under T_H1 conditions. Thus, most human CD4⁺ T cells retain both memory and flexibility of cytokine gene expression.