The incidence of Clostridium difficile infection (CDI) has increased since 2000, with greater numbers of severe cases reported, in part due to the emergence of a hypervirulent strain. Initial therapy with metronidazole is still recommended for mild to moderate CDI, but vancomycin is recommended for first-line therapy of severe CDI. Colectomy could be life-saving for some patients with severe disease that does not respond to maximal medical therapy. Recurrent CDI is a challenge to treat; no single effective therapy currently exists. Treatments include antibiotics, adjunct probiotics, fecal microbiota transplant and immune approaches. This Review discusses the various therapeutic approaches used for the treatment of refractory and recurrent CDI.