Infection with Clostridioides difficile (commonly referred to as C. diff; formerly Clostridium difficile) is an extreme example of a type of gut microbiome dysbiosis that can occur in patients with cancer. C. diff is a gram-positive, anaerobic, spore-forming, toxigenic bacterium, and infection is acquired via fecal-oral transmission and can cause symptoms ranging from uncomplicated diarrhea to pseudomembranous colitis and toxic megacolon. Because of many common risk factors (e.g., use of antibiotic therapy, advanced age, exposure to healthcare environments, immunosuppression), the hematology and oncology population is at high risk for C. diff colonization or infection.