The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are leading causes of nosocomial infections worldwide, characterized by multidrug resistance. This review summarizes the known antimicrobial resistance mechanisms of these pathogens, which include drug inactivation/alteration, modification of drug binding sites, changes in cell permeability, and biofilm formation. Drug inactivation involves the production of enzymes like β-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferases. Modification of drug binding sites involves mutations in genes encoding penicillin-binding proteins (PBPs). Changes in cell permeability can occur through porin loss or increased expression of efflux pumps. Biofilm formation provides a mechanical and biochemical shield that reduces drug efficacy. The review also discusses the specific resistance mechanisms of each ESKAPE pathogen, highlighting the challenges they pose to public health and the need for new therapeutic strategies.The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are leading causes of nosocomial infections worldwide, characterized by multidrug resistance. This review summarizes the known antimicrobial resistance mechanisms of these pathogens, which include drug inactivation/alteration, modification of drug binding sites, changes in cell permeability, and biofilm formation. Drug inactivation involves the production of enzymes like β-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferases. Modification of drug binding sites involves mutations in genes encoding penicillin-binding proteins (PBPs). Changes in cell permeability can occur through porin loss or increased expression of efflux pumps. Biofilm formation provides a mechanical and biochemical shield that reduces drug efficacy. The review also discusses the specific resistance mechanisms of each ESKAPE pathogen, highlighting the challenges they pose to public health and the need for new therapeutic strategies.