Skeletal muscle regeneration is an efficient stem cell-based repair system that ensures healthy musculature. For this repair system to function continuously throughout life, muscle stem cells must contribute to the process of myofiber repair as well as repopulation of the stem cell niche. The decision made by the muscle stem cells to commit to the muscle repair or to remain a stem cell depends upon patterns of gene expression, a process regulated at the epigenetic level. Indeed, it is well accepted that dynamic changes in epigenetic landscapes to control DNA accessibility and expression is a critical component during myogenesis for the effective repair of damaged muscle. Changes in the epigenetic landscape are governed by various posttranslational histone tail modifications, nucleosome repositioning, and DNA methylation events which collectively allow the control of changes in transcription networks during transitions of satellite cells from a dormant quiescent state toward terminal differentiation. This chapter focuses upon the specific epigenetic changes that occur during muscle stem cell-mediated regeneration to ensure myofiber repair and continuity of the stem cell compartment. Furthermore, we explore open questions in the field that are expected to be important areas of exploration as we move toward a more thorough understanding of the epigenetic mechanism regulating muscle regeneration.