Antimicrobial resistance (AMR) in Clostridioides difficile remains a significant threat to global healthcare systems, not just for the treatment of C. difficile infection (CDI), but as a reservoir of AMR genes that could be potentially transferred to other pathogens. The mechanisms of resistance for several antimicrobials such as metronidazole and MLSB-class agents are only beginning to be elucidated, and increasingly, there is evidence that previously unconsidered mechanisms such as plasmid-mediated resistance may play an important role in AMR in this bacterium. In this review, the genetics of AMR in C. difficile will be described, along with a discussion of the factors contributing to the difficulty in clearly determining the true burden of AMR in C. difficile and how it affects the treatment of CDI.