Clostridioides difficile infection is the most common cause of infectious diarrhea in hospitals with an increasing incidence in the community. Clinical presentation of C difficile infection ranges from diarrhea manageable in the outpatient setting to fulminant infection requiring intensive care admission. There have been significant advances in the management of primary and recurrent C difficile infection including diagnostics, newer antibiotics, antibody treatments, and microbiome restoration therapies. Because of the risk of clinical false-positive results with the polymerase chain reaction test, a two-step assay combining an enzyme immune assay for glutamate dehydrogenase and the C difficile toxin is being used. Cost permitting, I treat a first episode of C difficile infection preferably with fidaxomicin over vancomycin but not metronidazole. The most common complication after C difficile infection is recurrence. I manage a first recurrence with a vancomycin taper and pulse or fidaxomicin and recommend a single dose of intravenous bezlotoxumab (a monoclonal antibody against the toxin B) to reduce recurrence rates for those patients at high risk. Patients with multiply recurrent C difficile infection are managed with a course of antibiotics such as vancomycin or fidaxomicin followed by microbiota restoration. The success of fecal microbiota transplantation is greater than 85%, compared with the 40% to 50% success rate of antibiotics in this situation. Fecal microbiota transplantation is heterogeneous and has rare but serious risks such as transmission of infections. Standardized microbiota restoration therapies are in clinical development and have completed phase III clinical trials. This review answers common clinical questions in the management of C difficile infection.