Clostridium difficile causes antibiotic- and healthcare-associated diarrhea, which is characterized by a high mortality rate (5–15%) and high recurrence rate of 20% or more. Therapeutic alternatives to antibiotics are urgently needed to improve the overall cure rate. Among these, therapeutic antibodies have shown promising results in clinical studies. Herein, the authors review current monoclonal and polyclonal anti- C. difficile antibodies that have entered the clinical development stage, either for systemic administration or by the oral route. The antibodies can be applied as monotherapy or in combination with standard-of-care to treat an infection with C. difficile or to protect from a recurrence. Bezlotoxumab is the first antibody for secondary prevention of recurrence of C. difficile infection approved by the regulatory agencies in US and Europe. The human monoclonal antibody is administered systemically to patients receiving oral standard-of–care antibiotics. Other antibodies are currently in the clinical pipeline, and some are intended for oral use. They show a good safety profile, high efficacy and low production costs, and can be considered promising therapies of the future. The most promising orally administered drug candidate is a bovine antibody from hyperimmune colostral milk, which is in an advanced clinical development stage. Which antibody will enter the market is dependent on its bioavailability at the site of infection as well as its activity against C. difficile toxins, protection against colonization and possible action on spore formation. The antibody must demonstrate a clear benefit in comparison with other available treatment options to be considered for use by clinicians.