Free-radical biology, which is central to the fields of radiation, aging and xenobiotics, has shifted from a paradigm highlighting damage to a paradigm emphasizing the role of free radicals in regulatory processes. A unified approach is possible since multiple stressors tend to activate a coordinated set of common mechanisms. These include antioxidant defenses, metal chelators, DNA repair systems, heat-shock proteins, xenobiotic efflux transporters, protein degradation systems, cell survival and apoptosis pathways and detoxification systems. Nearly all MAPK signal transduction pathways employ oxidative signaling, largely generated via membrane-bound NADPH oxidase systems. These regulate most cellular stress, growth and apoptotic responses. A new global perspective highlighting “Electroplasmic Cycles” incorporates numerous cellular aspects of control including free radicals, protein and histone modifications, nuclear–cytoplasmic transport, and ion channels. Aspects critical to multiple stressors include complex interactions related to apoptosis-necrosis, immunological responses (Toll-like receptors), bystander effects, chaperone proteins, and multiple xenobiotic efflux proteins. The synthesis suggests that a systems approach to multiple stressor impacts is required since understanding requires holistic appreciation of integrated regulatory circuitry.