This dissertation, by Thomas Barton Suter, discusses enhancer function driving cellular senescence, DNA damage repair, differentiation, and nuclear organization. Enhancers are a major regulatory feature of epigenomic regulation, and play a diverse array of functions. In the first chapter, I discuss the background of cellular senescence and the epigenomic modifications that are known to play a role in this process, including marks associated with enhancer function. In the second chapter, I provide primary evidence of the key role enhancers play in driving the senescence phenotype. In the third chapter, I discuss the role that DNA damage and repair plays in nuclear receptor activity at enhancers. In the fourth chapter, I discuss the mechanisms by which regions in embryonic stem cells can be marked for later activation in future cell fates. In the fifth chapter, I present a study showing the role enhancers can play in nucleating nuclear organization.