Activation of T cells is an essential step in the immunological response to infection. Although activation of naïve T cells results in proliferation and slow differentiation into cytokine-producing effector cells, antigen engagement with memory cells leads to cytokine production immediately. Even though the cell surface signaling events are similar in both the cases, the outcome is different, suggesting that distinct regulatory mechanisms may exist downstream of the activation signals. Recent advances in the understanding of global epigenetic patterns in T cells have resulted in the appreciation of the role of epigenetic mechanisms in processes such as activation and differentiation. In this review we discuss recent data suggesting that naïve T cell activation, differentiation, and lineage commitment result in epigenetic changes and a fine balance between different histone modifications is required. On the other hand, memory T cells are poised and do not require epigenetic changes for short-term activation.