Oxygen is an essential element for life, which is mostly consumed at mitochondria for energy metabolism. For the genome inside nucleus, oxygen conducts structural regulations and chemical modifications through multiple pathways, where reactive oxygen species (ROS) serve as important messenger molecules. The highly activated ROS have the ability to produce different kinds of DNA lesions, while ferrous ions provide supports in many forms. Under the combinatorial action of oxygen and iron, almost all the genomic biochemical processes, such as replication, transcription and DNA damage repair are affected. Moreover, the variation of environmental oxygen concentration, particularly hypoxia that presents in many major diseases and critical physiological stages, provokes the responds at the genomic level. While the factors that lead to these genomic alterations are potential drug targets and deserve systematic investigations, herein, we collect the existing knowledge in the effects of ROS, ferrous ion and cell hypoxia on genome, along with brief discussions of the related drug molecules.