ABSTRACT Siderophore cephalosporins are designed to exploit bacterial nutrient uptake systems to gain accelerated uptake across the outer membrane of Gram-negative bacteria. They contain iron (III) binding motifs that allow them to form complexes that will be recognized as potential substrates by iron-siderophore transport systems. Research during the last five decades has culminated in the approval for clinical use of the siderophore cephalosporin cefiderocol, which incorporates accumulated learning from investigations of structural features that enhance resistance toward hydrolysis by β-lactamases, that promote bacterial membrane permeability, and that confer long pharmacokinetic half-life in the human host.