Clostridium difficile infections (CDIs) have emerged as one of the principal threats to the health of hospitalized and immunocompromised patients. The importance of C difficile colonization is increasingly recognized not only as a source for false-positive clinical testing but also as a source of new infections within hospitals and other health care environments. In the last five years, several new treatment strategies that capitalize on the increasing understanding of the altered microbiome and host defenses in patients with CDI have completed clinical trials, including fecal microbiota transplantation. This article highlights the changing epidemiology, laboratory diagnostics, pathogenesis, and treatment of CDI.