A recent article published in Medicine and Infectious Diseases reported that Clostridium difficile – an anaerobic spore-forming Gram-positive bacillus, is recognized as an evolving international health problem. The authors stated that until recently, metronidazole and vancomycin were the only drugs available to treat C. difficile infection (CDI), but a better knowledge of the pathophysiology and development of new drugs have completely modified the management of initial episodes and recurrences of CDI. It has been found that fidaxomicin can significantly reduce recurrences compared to vancomycin. Meanwhile, new drugs like cadazolid, surotomycin, ridinilazole, and rifaximin are also being evaluated. Moreover, gut microbiota homeostasis has been proven be a key determinant in recurrences of CDI, as demonstrated by the development of gut microbiota transplantation and alternative microbiota substitution. While passive immunotherapy and vaccinal approaches are also currently being evaluated. This article summarized that CDI treatment has evolved with the development of new therapeutic pathways which require implementation in international guidelines.