Cefiderocol represents a significant advancement in the treatment of multidrug-resistant Gram-negative bacterial infections. Its unique uptake mechanism, leveraging bacterial iron transport pathways for membrane permeation, sets it apart from conventional β-lactam antibiotics. Through its siderophore-mediated drug uptake, cefiderocol efficiently bypasses outer membrane barriers, allowing it to target and penetrate resistant pathogens, including those resistant to carbapenems and other antibiotics. This distinct property positions cefiderocol as a promising therapeutic option for infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales. Despite its promise, resistance to cefiderocol is emerging, driven by mutations in penicillin-binding proteins, impaired siderophore transporter systems, and β-lactamase production. These mechanisms disrupt antibiotic binding, compromise iron transport, and enzymatically inactivate cefiderocol, respectively, limiting its efficacy. This review examines cefiderocol's innovative mode of entry, therapeutic potential, and the challenges posed by resistance, offering insights into its role in the fight against multidrug-resistant pathogens.