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Phagocytic leukocytes generate reactive oxygen species important for the killing of invading microorganisms. The source of these oxidants is the NADPH oxidase, a tightly controlled multicomponent enzyme made up of a membrane-associated catalytic moiety and cytosolic regulatory components that must assemble to form the active oxidase. The phagocyte NADPH oxidase was the first mammalian system shown to be directly regulated by a Rac GTPase. We review here our understanding of NADPH oxidase regulation by Rac, as well as the regulation of Rac itself, in phagocytic leukocytes. Rather than viewing Rac as a "cog" in the NADPH oxidase machinery, we argue for a view of Rac GTPases as critical "molecular switches" regulating the formation of ROS by phagocytic leukocytes under physiologic and pathologic conditions.