Host defense responses against microbes are most often thought of in terms of effectors of microbial destruction. However, recent evidence demonstrates that the more complex interactions between the microbiota and innate immune mechanisms, such as the inflammasome-mediated response, cannot be readily explained within just the traditional paradigms of microbial killing mechanisms. In this review, the concepts of both resistance and tolerance are applied to inflammasome-microbiota interactions, and the various physiological consequences of this interplay, including roles in inflammation, tissue repair, tumorigenesis, and metabolism, are discussed.