Using highly conserved, complex enzyme systems, leukocytes utilize the toxic nature of free radical intermediates, derived from oxygen and nitrogen, to control microbial pathogens as part of the innate immune response. Upon activation, NADPH oxidase generates superoxide anion radicals, which in turn give rise to further reactive oxygen intermediates. Similarly, activated nitric oxide synthase 2 catalyses the production of nitric oxide radicals, which leads to the formation of reactive nitrogen intermediates. Nitrogen- and oxygen-centered reactive intermediates can interact to form further reactive species. In addition, presence of the cationic transporter, Nrampl, may exacerbate the effects of these toxic compounds on invading microbes. While each of these antimicrobial systems can operate independently, the combination of their activities is synergistic in the successful containment of almost all invading pathogens. These systems are activated and modulated by microbial products and a series of temporally expressed cytokines. They also feed directly into the initiation of the adaptive immune response, which culminates in lasting specific immunity. The effector molecules, generated in the early innate immune response, are not specific to the invading pathogen and may also cause damage to the host. It is the critical balance of these processes in the initial stages of infection that determines the outcome of infectious disease.