Clostridium difficile is the causal agent of antibiotic-associated diarrhea and is a leading cause of hospital-acquired infections in the US. C. difficile has been known to cause severe diarrhea and colitis for more than 30 years, but the emergence of a newer, hypervirulent strain of C. difficile (BI/NAP1) has further compounded the problem, and recently both the number of cases and mortality associated with C. difficile-associated diarrhea have been increasing. One of the major drivers of disease pathogenesis is believed to be an excessive host inflammatory response. A better understanding of the host inflammation and immune mechanisms that modulate the course of disease and control host susceptibility to C. difficile could lead to novel (host-targeted) strategies for combating the challenges posed by this deadly infection. This review summarizes our current knowledge of the host inflammatory response during C. difficile infection.