Cefiderocol is a novel siderophore cephalosporin that has gained attention for its potent activity against multidrug-resistant (MDR) Gram-negative pathogens, making it a valuable addition to the antimicrobial armamentarium. Its efficacy in treating complicated urinary tract infections (cUTIs) and nosocomial pneumonia has been well-established, although challenges remain regarding its role in Acinetobacter baumannii infections and the possible emergence of resistance. The decision to use cefiderocol as a monotherapy or in combination should be guided by pathogen susceptibility, clinical severity, and local epidemiology. Then, the potential to serve as an effective empirical therapy, careful stewardship, and further research are essential to maximize its therapeutic benefits and ensure its long-term efficacy. This review explores the efficacy of cefiderocol, resistance development, heteroresistance, its use as monotherapy or in combination therapy, and its role in empirical treatment regimens. We discuss data about clinical trials and real-world evidence to assess the future role of cefiderocol in antibiotic regimens.