<p>Antimicrobial Resistance (AMR) represents a defining crisis of modern healthcare, severely limiting therapeutic options and driving a global increase in clinical mortality. Central to this crisis is <i>Klebsiella pneumoniae</i>, a ubiquitous gut commensal that has evolved into a formidable opportunistic pathogen through its remarkable ability to transition from a harmless organism to a hypervirulent, Multidrug-Resistant (MDR) threat. This review examines that pathogenic transition, emphasizing the dangerous convergence of virulence and resistance traits particularly within carbapenem-resistant lineages. The bacterium leverages an expansive “open” pangenome and immense genetic plasticity to act as a primary trafficker of AMR genes. We detail the molecular mechanisms underlying resistance across nearly all antibiotic classes including β-lactams, aminoglycosides, and last-resort polymyxins driven by enzymatic degradation, target modification, and sophisticated efflux systems. Beyond clinical antibiotic pressure, the review explores how non-antibiotic drivers, such as environmental stressors, biocide exposure, and heavy metals, accelerate AMR evolution through cross-resistance and novel epigenetic adaptations. The rapid dissemination of these resistance determinants is facilitated by a robust toolkit of Horizontal Gene Transfer (HGT), including transposons, integrons, plasmid replicons, and bacteriophage-mediated transduction. Finally, this review evaluates the current therapeutic landscape, addressing the challenges of the drug development pipeline while highlighting emerging interventions such as novel β-lactam/β-lactamase inhibitor combinations, phage therapy, and anti-virulence strategies. Understanding this interplay between genomic evolution and ecological drivers is critical for designing a unified stewardship framework and effective interventions to curb the global AMR crisis.</p>