Antibiotics have significant and long-lasting effects on the intestinal microbiota and consequently reduce colonization resistance against pathogens, including Clostridium difficile. By altering the community structure of the gut microbiome, antibiotics alter the intestinal metabolome, which includes both host- and microbe-derived metabolites. The mechanisms by which antibiotics reduce colonization resistance against C. difficile are unknown yet important for development of preventative and therapeutic approaches against this pathogen. This review focuses on how antibiotics alter the structure of the gut microbiota and how this alters microbial metabolism in the intestine. Interactions between gut microbial products and C. difficile spore germination, growth, and toxin production are discussed. New bacterial therapies to restore changes in bacteria-driven intestinal metabolism following antibiotics will have important applications for treatment and prevention of C. difficile infection.