Increasing understanding of the normal commensal microorganisms in humans suggests that restoring and maintaining the microbiome may provide a key to preventing colonization and infection with multidrug-resistant organisms (MDROs). Intact communities of commensals can prevent colonization with MDROs through both competition for space and resources and the complex immunologic and biochemical interactions that have developed between commensal and host over millennia. Current antimicrobials, however, exert tremendous collateral damage to the human microbiome through overuse and broadening spectrum, which has likely been the driving force behind the introduction and proliferation of MDROs. The future direction of infection control and anti-infective therapy will likely capitalize on an expanding understanding of the protective role of the microbiome by (1) developing and using more microbiome-sparing antimicrobial therapy, (2) developing techniques to maintain and restore indigenous microbiota, and (3) discovering and exploiting host protective mechanisms normally afforded by an intact microbiome.