The rapid worldwide spread of antimicrobial resistance among gram-negative bacteria is driven by a complex interplay of human, environmental, and health care–associated factors and accelerated by mobile genetic elements that facilitate the dissemination of resistance genes. Resistance in gram-negative bacteria arises primarily through reduced drug entry, active drug efflux, modification of antibiotic targets, and enzymatic drug inactivation, most notably through β-lactamase production. Clinically important resistant pathogens include extended-spectrum β-lactamase–producing Enterobacterales, carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa with difficult-to-treat resistance, and carbapenem-resistant Acinetobacter baumannii.