For many years microglia, the resident CNS macrophages, have been considered only in the context of pathology, but microglia are also glia cells with important physiological functions. Microglia-derived oxidant production by NADPH oxidase (NOX2) is implicated in many CNS disorders. Oxidants don't stand alone however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defense mechanism, and further, we discuss in the context of protein thiolation of target redox proteins the necessity for tightly localized, timed, and confined oxidant production to work in concert with antioxidant proteins to promote redox signaling. NOX2-mediated redox signaling modulate the acquisition of the classical or alternative microglia activation phenotypes by regulating major transcriptional programs mediated through NFkB and Nrf2, major regulators of the inflammatory and antioxidant response, respectively. As both antioxidants and NOX-derived oxidants are co-secreted, in some instances redox signaling may extend to neighboring cells through modification of surface or cytosolic target proteins. We consider a role for microglia NOX-derived oxidants in paracrine modification of synaptic function through long term depression and in the communication with the adaptive immune system. There is little doubt that a continued foray into the functions of the antioxidant response in microglia will reveal antioxidant proteins as dynamic players in redox signaling, which in concert with NOX-derived oxidants fulfill important roles in the autocrine or paracrine regulation of essential enzymes or transcriptional programs. This article is protected by copyright. All rights reserved.