Clostridioides difficile (C. difficile) has become a pathogen of worldwide importance considering that epidemic strains are disseminated in hospitals of several countries, where community-acquired infections act as a constant source of new C. difficile strains into hospitals. Despite the advances in the treatment of infections, more effective therapies against C. difficile are needed but, at the same time, these therapies should be less harmful to the resident gastrointestinal microbiota. The purpose of this review is to present a description of issues associated to C. difficile infection, a summary of current therapies and those in developmental stage, and a discussion of potential combinations that may lead to an increased efficacy of C. difficile infection treatment.