Summary: Recent findings suggest a new paradigm that early inflammatory cytokines promote the effector T-cell response while inhibiting the development of CD8+ T-cell memory. Although this opposing effect may appear paradoxical at first, it makes biological sense in the context of an infection, by ensuring a maximal effector response that will clear the pathogen. Once infection is controlled, the withdrawal of inflammatory cytokines allows the differentiation of effectors into long-lived memory cells that provide protective immunity against re-infection. Memory T cells differ from naïve T cells in their responsiveness to stimulation, which leads to the rapid expression of effector functions. The molecular basis for enhanced functionality of memory T cells remains largely unknown. Recent results indicate that certain epigenetic changes are imprinted in memory T cells that play an important role in keeping them poised to respond immediately upon antigen re-encounter. These epigenetic modifications occur as naïve T cells become activated and are influenced by factors that regulate memory formation. Thus, epigenetic changes are an integral component of memory T-cell differentiation, while inflammation plays an unexpected regulatory role in the process. These advances in our understanding of T-cell memory will undoubtedly help design unconventional vaccine strategies for inducing large populations of long-lived and functional memory CD8+ T cells.