The human microbiome constitutes the collection of all the microorganisms living in association with the human body with each body site being home to a unique microbial community. Human-associated microbial communities can include eukaryotes, archaea, bacteria, and viruses and provide protection against foreign invaders, stimulate the immune response, produce antimicrobials, and aid in digestion among other functions. Our understanding of the link between the human microbiome and disease is rapidly expanding in large part due to revolutionizing advances in next generation sequencing. In fact, an ever-growing number of studies have demonstrated that changes in the composition of our microbiomes correlate with numerous disease states or responses to treatment. However, understanding the impact of shifts in microbial communities on health and disease and the mechanisms that confer stability in the microbiome have been challenging to elucidate, due to the vast microbial diversity and differences between individuals. Nevertheless, the notion that manipulation of microbial communities may provide prophylactic or therapeutic tools to improve human health has been the focus of much research. Here, we highlight a collection of Pearls articles delving into the current state of knowledge linking the microbiome to human disease.