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The human body teems with microbial hitchhikers. Most are harmless as long as they stay where they belong, such as on the skin or in the intestines, and some are even beneficial to their unsuspecting hosts. Consequently, organisms that are part of the normal human microbiota typically exist in a symbiotic relationship with us. Of course, the human body is also under constant attack from microbial invaders that inhabit the surrounding environment. Fortunately, we have developed a series of barriers and elaborate mechanisms that keep normal microbes and invading pathogens at bay. Obstacles such as skin and stomach acid will repel most microorganisms; these are considered nonspecific defenses. But for those microbes able to breach these barriers, there await adaptive and nonadaptive immune defenses. This chapter describes the general protective mechanisms of the innate immune response which provide an effective first line of defense against potential pathogens.