Fidaxomicin, a nonabsorbed macrocyclic compound, is the first antimicrobial agent approved by the FDA for the treatment of Clostridium difficile infection (CDI) in adults over the last 25 years. It is bactericidal, and its mechanism of action relates to inhibition of a RNA polymerase at a site distinct from where rifamycins interact. Fidaxomicin, 200 milligrams by mouth twice daily, is not inferior to vancomycin, 125 milligrams by mouth 4 times daily, for treatment of CDI as determined by clinical response after 10 days of treatment and is superior to vancomycin for sustained response without recurrence 25 days after treatment completion. These results are a significant advance in the treatment of CDI and herald the development of narrow-spectrum anti-C. difficile agents that relatively spare the indigenous fecal microbiota. Continued vigilance for the development of resistance and unanticipated side affects will be important as the drug is introduced into clinical practice.