Clostridium difficile (CD) is a major cause of morbidity and mortality in hospitalized patients. Over the last decade, researchers have begun to reassess the traditional infection prevention model for this infection. Data suggesting a greater role for asymptomatic shedders has increased our understanding of current vertical prevention techniques and is forcing researchers to look more at new processes and technologies to decrease disease incidence. This review addresses current controversies in infection prevention for CD such as contact precautions, hand hygiene, environmental disinfection and diagnostic testing. The review also summarizes recent literature on promising new techniques like CD screening of asymptomatic carriers, supplemental environmental cleaning technologies, vaccines and the manipulation of the intestinal microbiome.