Bacterial resistance to carbapenem agents has reached alarming levels. Accordingly, collaborative efforts between national and international organizations and the pharmaceutical industry have led to an impressive expansion of commercially available β-lactam agents in recent years. No available agent comes close to the broad range of activity afforded by cefiderocol, a novel siderophore-cephalosporin conjugate. The novelty of and need for cefiderocol are clear, but available clinical data are conflicting, leaving infectious diseases specialists puzzled as to when to prescribe this agent in clinical practice. After a brief overview of cefiderocol pharmacokinetics and pharmacodynamics, safety data, cefiderocol susceptibility testing, and putative mechanisms of cefiderocol resistance, this review focuses on determining cefiderocol’s role in the management of specific pathogens, including carbapenem-resistant Acinetobacter baumannii complex, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and less commonly identified glucose-nonfermenting organisms such as Stenotrophomonas maltophilia, Burkholderia species, and Achromobacter species. Available preclinical, clinical trial, and postmarketing data are summarized for each organism, and each section concludes with our opinions on where to position cefiderocol as a clinical therapeutic.