© 2016 by Taylor & Francis Group, LLC. Oxidative stress and ROS accumulation are major events involved in the life and death of cells. At low levels, ROS are involved in intracellular pathways but their accumulation can lead to deleterious effects, such as genotoxic stress or metabolic dysregulation, and to initiation or development of pathologies. Therefore, the pathways involved in ROS production and antioxidant response play a major role in the maintenance of cell homeostasis. Gene expression and regulation has been described as a major regulator of the response to oxidative stress, but many questions remain to fully characterize the gene response to oxidative stress. For example, the regulation of ROS production by epigenetic regulation of target genes or the effect of ROS accumulation on epigenetic modifications is still unclear. The link between ROS, mitochondria metabolism, and its effect on nuclear gene regulation are also under investigation. In this chapter, we highlight studies on the role of mitochondrial metabolism in ROS production and the effect of ROS on nuclear epigenetic modifications (DNA methylation and histone modifications). We also discuss the control of ROS production by the epigenetic regulation of genes involved in redox signaling, and the therapeutic potential of epigenetic-targeting drugs.