In recent years, significant advances in the treatment of Clostridium difficile infection (CDI) have risen. We review the most relevant updated recommendations in the current standard of care of CDI and discuss emerging therapies, including antibiotic, alternative therapies (probiotics, toxin-binding resins, immunotherapy) and new data on fecal transplantation. Upcoming surgical options and other rescue therapies for severe refractory disease are also addressed. Although oral metronidazole is a first-line therapy for non-severe CDI, emerging data have demonstrated its inferiority relatively to vancomycin, particularly in the setting of recurrent and/or severe infection. After a CDI recurrence for the first time, fidaxomicin has been shown to be associated with lower likelihood of CDI recurrence compared to vancomycin. Fecal transplantation is now strongly recommended for multiple recurrent CDI and may have a role in refractory disease. Oral, frozen stool capsules may simplify fecal transplantation in the future, with preliminary promising results. Diverting loop ileostomy combined with colonic lavage is a potential alternative to colectomy in severe complicated CDI. Potential alternative therapies requiring further investigation include toxin-binding resins and immunotherapy.