In this issue of Gastroenterology Clinics, guest editors Dr. Colleen R. Kelly brings her considerable expertise to the topic of Mastering Clostridioides difficile Infection:: Comprehensive Insights and Patient-Focused Care. Increasing rates of C. difficile infection, specifically community-acquired and multiply recurrent infections, have occurred over the past 20 years. In the era of nucleic acid amplification-based testing, diagnostic challenges have become apparent, and making an accurate diagnosis is important given newer therapeutic options for treatment and prevention of recurrence. This issue provides the most current information on management of C. difficile infection with the goal of improving patient outcomes.