Following antigen recognition, CD8+ T lymphocytes can follow different patterns of differentiation, with the generation of different subsets characterized by distinct phenotypes, functions, and migration properties. The changes of transcription factors activity and chromatin structure dynamics drive the functional differentiation and phenotypic heterogeneity of these T cell subsets, which include short-lived effectors, long-term survival of memory, and also dysfunctional exhausted T cells. Recent progress in the field has shed light on the key contribution of chromatin organization to control the T cell fate specification. In fact, the understanding of these processes has important implications for the development of new immunotherapy protocols and to design new vaccination strategies. Here, we review the current understanding of the contribution of chromatin architecture and transcription factor activity orchestrating the gene expression programs guiding the CD8+ T cell subset commitment. We will focus on epigenetic changes, acting sequentially or in combination, which control the transcriptional programs governing T cell plasticity, stability, and memory. New molecular insights into the mechanisms of maintenance of cellular memory and identity, favoring or impeding the reprogramming, will be discussed in the context of T cell memory differentiation in infection and cancer.