Recorded observations indicating an association between intestinal microbes and health are long-standing in terms of specific diseases, but emerging high-throughput technologies that characterize microbial communities in the intestinal tract are suggesting new roles for the supposedly normal microbiome. This review considers the nature of the evidence supporting a relationship between the microbiota and the predisposition to disease as associative, correlative, or causal. Altogether, indirect or associative support currently dominates the evidence base, which now suggests that the intestinal microbiome can be linked to a growing number of over 25 diseases or syndromes. While only a handful of cause-and-effect studies have been performed, this form of evidence is increasing. The results of such studies are expected to be useful in monitoring disease development, in providing a basis for personalized treatments, and in indicating future therapeutic avenues.