Clostridioides difficile is the leading cause of hospital-acquired gastrointestinal infections and a major public health burden in the United States. C. difficile infection causes a spectrum of disease from mild diarrhea to severe complications such as pseudomembranous colitis, toxic megacolon and death. This broad range of disease is only partially explained by bacterial genetic factors, host genetics, comorbidities and previous drug exposures. Another important factor is the gut microbiome, the disruption of which results in a loss of colonization resistance to C. difficile. Here, we review how gut microbiota and their metabolites impact C. difficile virulence and influence disease.