Antimicrobial resistance poses a major global health challenge, and infections caused by multidrug-resistant Gram-negative bacteria are associated with substantial morbidity and mortality. In contrast to many Gram-positive pathogens, Gram-negative bacteria combine intrinsic barriers with acquired determinants, including enzymatic drug inactivation, reduced outer membrane permeability, active efflux, and target modifications, which collectively compromise the efficacy of multiple antibiotic classes. Previous reviews have largely catalogued resistant pathogens or antimicrobial agents. This review provides a mechanism-focused overview of antimicrobial resistance in clinically important Gram-negative bacteria and explains how dominant resistance determinants translate into clinically relevant failure modes, such as delayed effective therapy, limited treatment options, and increased reliance on toxic last-line agents. Current and emerging therapeutic strategies are discussed through a mechanism-based lens, emphasizing newer β-lactam/β-lactamase inhibitor combinations and nontraditional approaches, including phages, antivirulence, and microbiome-based interventions. This review highlights the conceptual links between resistance mechanisms, clinical impact, and rational therapeutic choices and identifies priorities for future research aimed at mitigating antimicrobial-resistant Gram-negative infections.