Metastasis is responsible for the vast majority of cancer-related deaths. However, our understanding of this complex process is still vastly limited, as is the ability to prevent metastasis. Paradoxically, while clinical trials are commonly performed in patients with advanced metastatic disease, disseminated residual disease is rarely targeted. This eliminates a critical window of opportunity to prevent metastasis. Disseminated tumor cells (DTCs) that seed metastases can remain undetected years to decades after treatment of the primary tumor. Late relapse may be due to the ability of DTCs to survive in a quiescent or dormant state and evade therapies. Quiescence, a reversible growth arrest coupled to robust survival, has emerged as a ftting biological defnition for dormancy of single DTCs, but these mechanism remain as one of the least understood “black boxes” in cancer biology. Because of the reversible nature of dormancy, it has been proposed that epigenetic changes are key in regulating the onset, maintenance and reactivation from this state. This is mediated by the post-translational modifcation of histones (PTMs), ATP-dependent chromatin remodeling, DNA methylation, and the incorporation of specialized histone variants into chromatin. Many morphogenetic and micro-environmental cues like retinoic acid, TGFβs, hematopoietic stem cell dormancy regulating cues and BMPs are known to cause chromatin modifcations that dictate cell fate; these same cues were linked to the induction of cancer cell dormancy. Despite progress in understanding cancer cell dormancy, key questions remain open regarding its epigenetic nature. In this chapter we attempt to address key questions related to this topic using available data or hypothetical scenarios to build a model to further dissect how cancer cell dormancy can be manipulated epigenetically as a therapeutic strategy.