Reactive oxygen species (ROS), highly reactive molecules, are produced by living organisms as a result ofnormal cellular metabolism and environmental factors, and can damage nucleic acids and proteins, therebyaltering their functions. The human body has several mechanisms to counteract oxidative stress by producingantioxidants. A shift in the balance between oxidants and antioxidants in favor of oxidants is termed as “oxidativestress”. Paradoxically, there is a large body of research demonstrating the general effect of oxidative stress onsignaling pathways, less is known about the initial and direct regulation of signaling molecules by ROS, orwhat we term the “oxidative interface.” This review focuses on the molecular mechanisms through which ROSdirectly interact with critical signaling molecules to initiate signaling in a broad variety of cellular processes,such as proliferation and survival (MAP kinases and PI3 kinase), ROS homeostasis, and antioxidant generegulation (Ref-1 and Nrf-2). This review also deals with classification as well as mechanisms of formation offree radicals, examining their beneficial and deleterious effects on cellular activities and focusing on the potentialrole of antioxidants in preventing and repairing damage caused by oxidative stress. A discussion of the role ofphytochemical antioxidants in oxidative stress, disease and the epigenome is included.