As resources become more and more constrained in healthcare facilities around the world, we need to think in terms of both effectiveness, and cost-effectiveness. A new modelling study published in PLoS ONE evaluates the cost-effectiveness of several strategies to prevent the transmission of C. difficile. Probably the key finding of the study is that hand hygiene compliance, environmental decontamination, and empiric isolation and treatment were the most effective interventions. The model was a simulation of C. difficile transmission, including estimates for the following parameters: interactions between patients and health care workers; room contamination via C. difficile shedding; C. difficile hand carriage and removal via hand hygiene; patient acquisition of C. difficile via contact with contaminated rooms or health care workers; and patient antimicrobial use. Six interventions were then tested either individually or as a bundle at three levels of efficacy (base-case (BASE) to reflect typical hospital practice, intervention (INT) to represent implementation of hospital-wide efforts to reduce C. diffiicle transmission, and optimal (OPT) to represent the highest expected results from strong adherence to the interventions), and at three levels of transmission and importation (low, medium, and high). Bundled interventions were most cost-effective, and hand hygiene compliance, environmental decontamination, and empiric isolation and treatment were most effective as individual interventions. This study supports most approaches to C. difficile management, which recommend a bundle of interventions including focus on hand and environmental hygiene, and patient isolation.