AbstractClostridioides difficile(formerlyClostridium) is a major cause of healthcare associated diarrhea, and is increasingly present in the community. Historically,C difficileinfection was considered easy to diagnose and treat. Over the past two decades, however, diagnostic techniques have changed in line with a greater understanding of the physiopathology ofC difficileinfection and the use of new therapeutic molecules. The evolution of diagnosis showed there was an important under- and misdiagnosis ofC difficileinfection, emphasizing the importance of algorithms recommended by European and North American infectious diseases societies to obtain a reliable diagnosis. Previously, metronidazole was considered the reference drug to treatC difficileinfection, but more recently vancomycin and other newer drugs are shown to have higher cure rates. Recurrence of infection represents a key parameter in the evaluation of new drugs, and the challenge is to target the right population with the adapted therapeutic molecule. In multiple recurrences, fecal microbiota transplantation is recommended. New approaches, including antibodies, vaccines, and new molecules are already available or in the pipeline, but more data are needed to support the inclusion of these in practice guidelines. This review aims to provide a baseline for clinicians to understand and stratify their choice in the diagnosis and treatment ofC difficileinfection based on the most recent data available.