Clostridium difficile is the most common cause of infectious diarrhea in adults healthcare institutions. Recent studies have shown an increase in the incidence, severity and recurrence of C. difficile infection (CDI). Factors associated with the patient and medical care provided contribute to establishing colonization and, in some cases, subsequent progression to symptomatic disease. The availability of new microbiological techniques has contributed greatly to improving care for these patients. A diagnostic algorithm is provided for cases in which CDI is suspected based on current evidence regarding the effectiveness of microbiological and radiological methods. In cases in which CDI is confirmed, the first and most effective measure is the withdrawal of any antibiotic treatment the patient is receiving, if possible. The antimicrobial treatment of CDI is based on three classic agents: metronidazole, vancomycin and teicoplanin, along with the recent addition of fidaxomicin. Patients presenting serious symptoms, in addition to appropriate support and monitoring measures, may require surgical treatment. Infection prevention and control strategies can interrupt the transmission mechanism. This manuscript reviews current evidence on the approach of this entity from a multidisciplinary point of view.