There has been an increase in Clostridium difficile infection (CDI) incidence, severity, and mortality during the last decade. Although the elderly receiving antibiotic therapy are the most common group at risk for infection, CDI occurs in all age groups, and recent data indicate that CDI is emerging in groups that have been traditionally considered at low risk for infection. Additionally, approximately one-third of all CDI cases are now considered to be community associated in the U.S. New information is emerging on risk factors for an initial episode of CDI as well as recurrent disease. Increases in the burden of disease and severe outcomes related to CDI has been associated with the emergence of a new epidemic strain, restriction enzyme analysis BI, North American Pulsed-Field Type 1, and PCR Ribotype 027 (BI/NAP1/027) as well as other emerging strains. This article explores the changing epidemiology of CDI based on the latest available data as well as the recent developments in diagnosis and infection control.