Adaptive immunity to intracellular pathogens and tumors is mediated by antigen-experienced CD8 T cells. Individual naive CD8 T cells have the potential to differentiate into a diverse array of antigen-experienced subsets that exhibit distinct effector functions, life spans, anatomic positioning, and potential for regenerating an entirely new immune response during iterative pathogenic exposures. The developmental process by which activated naive cells undergo diversification involves regulation of chromatin structure and transcription but is not entirely understood. This review examines how alterations in chromatin structure, transcription factor binding, extracellular signals, and single-cell gene expression explain the differential development of distinct effector (T ) and memory (T ) CD8 T cell subsets. Special emphasis is placed on how Runx proteins function with additional transcription factors to pioneer changes in chromatin accessibility and drive transcriptional programs that establish the core attributes of cytotoxic T lymphocytes, subdivide circulating and non-circulating T cell subsets, and govern terminal differentiation. The discussion integrates the roles of specific cytokine signals, transcriptional circuits and how regulation of individual nucleosomes and RNA polymerase II activity can contribute to the process of differentiation. A model that integrates many of these features is discussed to conceptualize how activated CD8 T cells arrive at their fates.