Humans have coevolved with their microbes over thousands of years, but this relationship, is now being dramatically affected by shifts in the collective human microbiome resulting from changes in the environment and societal norms. Resulting perturbations of intestinal host-microbe interactions can lead to miscues and altered host responses that increase the risk of pathogenic processes and promote “western” disorders such as inflammatory bowel diseases, cancers, obesity, diabetes, autism, and asthma. Given the current challenges and limitations in gene therapy, approaches that can reshape the gut microbiome represent a reasonable strategy for restoring the balance between host and microbes. In this review and commentary, we highlight recent progress in our understanding of the intestinal microbiome in the context of health and diseases, focusing on mechanistic concepts that underlie the complex relationships between host and microbes. Despite these gains, many challenges lie ahead that make it difficult to close the gap between the basic sciences and clinical application. We will discuss the potential therapeutic strategies that can be used to manipulate the gut microbiota, recognizing that the promise of pharmabiotics (“bugs to drugs”) is unlikely to be completely fulfilled without a greater understanding of enteric microbiota and its impact on mammalian physiology. By leveraging the knowledge gained through these studies, we will be prepared to enter the era of personalized medicine where clinical inventions can be custom-tailored to individual patients to achieve better outcomes.