Stenotrophomonas maltophilia is an emerging multidrug-resistant (MDR) pathogen that primarily causes healthcare-associated infections. This bacterium employs two key resistance mechanismsintrinsic and acquired-to withstand antimicrobial toxicity, facilitating its spread and persistence within healthcare settings. This review focuses on acquired resistance mechanisms in S. maltophilia, highlighting genetic mutations and gene acquisition through horizontal gene transfer (HGT). Mutations that confer antimicrobial resistance commonly occur in drug targets (e.g., gyrA and parC, which encode DNA gyrase and topoisomerase IV, respectively), drug uptake systems, ribosomal proteins, metabolic enzymes, and more importantly, transcriptional regulators of multidrug efflux systems. These mutations can lead to resistance against the first-line treatments for S. maltophilia infections, including trimethoprim/ sulfamethoxazole, levofloxacin, cefiderocol, and minocycline. The acquisition of resistomes via HGT also occur in S. maltophilia. Resistance genes, such as those encoding sulfonamide resistance (sul), trimethoprim resistance (dfr), quinolone resistance (qnr), aminoglycoside-modifying enzymes, and multidrug/biocide efflux pumps can be transferred from neighboring microbial communities through various genetic vectors, including insertion sequences, transposons, gene cassettes/integrons, and conjugative plasmids. Intrinsic resistance, combined with acquired resistance, can transform S. maltophilia from an MDR pathogen into an extensively drug-resistant or even pandrug-resistant strain, thus further complicating its treatment and management.  Kulcsszavak: acquired resistance, antibiotic, antimicrobial, horizontal gene transfer, mutation, Stenotrophomonas maltophilia