Carbapenem-resistant Enterobacteriaceae are amongst the most feared pathogens due to severely limited treatment options. In response to this threat, three novel β-lactamase inhibitors have been developed in an attempt to reinvigorate and sustain our current antimicrobial therapies. Avibactam, vaborbactam, and relebactam are inhibitor agents with high affinity to Ambler class A and C β-lactamases and favorable outcomes in current clinical trials. However, although they do possess key similarities, these agents have unique differences which may have important clinical implications. The microbiologic spectrum, pharmacokinetics, and key clinical trials for each of these novel agents are reviewed. A proposed role in therapy and potential novel combinations are examined.