Advances in understanding the interaction between the human immune system and the microbiome have led to an improved understanding of the function of the vermiform appendix as a safe-house for beneficial bacteria in the colon. These advances have been made despite long standing clinical observations that the appendectomy is a safe and effective procedure. However, more recent clinical data show that an appendectomy puts patients at increased risk for recurrent Clostridium difficile (C. difficile)-associated colitis, and probably other diseases associated with an altered microbiome. At the same time, appendectomy does not apparently put patients at risk for an initial onset of C. difficile-associated colitis. These clinical observations point toward the idea that the vermiform appendix might not effectively protect the microbiome in the face of broad spectrum antibiotics, the use of which precedes the initial onset of C. difficile-associated colitis. Further, these observations point to the idea that historically important threats to the microbiome such as infectious gastrointestinal pathogens have been supplanted by other threats, particularly the use of broad spectrum antibiotics.