The incidence of Clostridium difficile infection continues to increase globally. Particularly concerning are hospital-acquired cases that attribute significant morbidity, mortality, and expenditures to the health care system. Proton pump inhibitors, which are widely prescribed and generally considered to have minimal adverse effects, have recently come under scrutiny for positive associations with C. difficile infection development. This article will specifically review the current state of evidence demonstrating a positive association between nosocomial proton pump inhibitor administration and the incidence of hospital-acquired C. difficile infection. In addition, the article delivers state-of-the-art knowledge relative to mechanisms by which proton pump inhibitor exposure may propagate the manifestation of C. difficile infection.