Clostridium difficile infections (CDI) are currently recognized as the leading cause of hospital-acquired diarrhea worldwide. CDIs begin with the ingestion of highly resistant Clostridium difficile spores. Bacterial communities found naturally in the gastrointestinal tract can provide a barrier against C. difficile colonization, thereby preventing CDI. With the current pharmaceutical advancements, exposure to several new broad-spectrum antibiotics can effectively disrupt and remove the protective barrier. As C. difficile spores travel through the gastrointestinal tract, the spores are able to germinate into actively growing cells, which can ultimately colonize a susceptible host. Due to the C. difficile’s lifecycle and its ability to form resistant spores, CDI is often difficult to treat, and the use of antimicrobials frequently results in relapse. The emergence of hypervirulent strains further highlights the need to address C. difficile infections. Research is currently geared toward developing novel antimicrobials that would specifically target C. difficile, as well as preventing C. difficile colonization.