The human body is host to 100 trillion gut microbes, approximately 10-times more than all human cells. It is estimated that the approximately 500-1000 species residing in the human gut encode 150-fold more unique genes than the human genome. The gut microbiota has important functions in metabolic processing, such as energy production, immune cell development, food digestion, and epithelial homeostasis. It has been increasingly recognized that a dysregulated gut microbiome contributes in a significant way to a variety of diseases, including diabetes, obesity, cardiovascular diseases, allergies, and inflammatory bowel disease. In particular, accumulating evidence indicates that functional interactions between the gut microbiome and xenobiotics play a role in mediating chemical toxicity and causing or exacerbating human disease. This review summarizes emerging evidence that illustrates how xenobiotics can affect the gut microbiome structure, create functional changes to the gut microbiome, and become biotransformed by the gut microbiome.