Many studies have connected epigenomic changes to substance abuse disorders. However, there is a key barrier to our understanding of the epigenome’s mechanistic roles. While epigenomic modifications have been widely mapped and correlated with changes in gene expression and cellular phenotypes, correlation does not demonstrate function or causation. This barrier arises because widely used techniques to perturb the epigenome, including pharmacological inhibition and genetic knock-outs or overexpressions, suffer from pleiotropic effects. Thus, it is unclear if epigenomic modifications drive, are a result of, or are simply associated with changes in gene states. Two important corollaries arise from this: 1) It is unclear whether and which epigenome modifications drive changes in gene expression, and 2) the temporal stability of epigenome modifications that would result in truly persistent “epigenetic” properties is unknown. The hypothesis of the proposed work is that the epigenome represents a powerful regulatory system layered on top of the genome, and by engineering new tools to interface with and control this system, we can harness its unique properties to understand and tackle substance abuse disorders. A guiding goal is to dissect the function of epigenome modifications from their form and demonstrate their specific relevance to substance abuse disorders. To achieve this, we will develop tools to sense and induce changes in the epigenome, and do so spatiotemporally in systems reflective of human genetics, epigenetics, and physiology.