There are 453K new C. difficile infections (CDI) every year and 83K recurrent infections, yet there are no licensed vaccines against this important nosocomial pathogen. The current pipeline of clinical-stage vaccines consists of two toxin-based candidates and one phase 3 candidate, which is no longer being pursued. Although mathematical studies and computer-simulation models suggest that a CDI vaccine would be a cost-effective approach to protect against disease, the overall public health impact for a CDI vaccine remains unclear. Moreover, there are gaps in our understanding of the mucosal immune responses against CDI and how immunity against nontoxin antigens can improve protection. This timely workshop will explore and identify high-priority knowledge gaps in C. difficile pathogenesis and immunology in order to establish a path for future CDI vaccine development, while considering the public health impact of introducing a licensed vaccine based on anti-toxin immunity.