The outer membrane (OM) of Gram-negative bacteria serves as a crucial barrier to antibiotics, with two primary pathways for antibiotic penetration: lipid-mediated for hydrophobic antibiotics and general diffusion porins for hydrophilic antibiotics. The OM's lipid and protein composition significantly influence bacterial sensitivity to antibiotics, and drug resistance often involves modifications to these components. This review discusses the molecular mechanisms of antibiotic permeation through the OM and the strategies bacteria use to resist antibiotics by altering these pathways. Key topics include the structure and function of OM lipids and porins, the impact of antibiotic resistance mechanisms on OM permeability, and the role of specific mutations and modifications in reducing antibiotic susceptibility. The review highlights the importance of understanding these mechanisms to develop more effective antibiotic therapies and new antibiotics targeting OM components.The outer membrane (OM) of Gram-negative bacteria serves as a crucial barrier to antibiotics, with two primary pathways for antibiotic penetration: lipid-mediated for hydrophobic antibiotics and general diffusion porins for hydrophilic antibiotics. The OM's lipid and protein composition significantly influence bacterial sensitivity to antibiotics, and drug resistance often involves modifications to these components. This review discusses the molecular mechanisms of antibiotic permeation through the OM and the strategies bacteria use to resist antibiotics by altering these pathways. Key topics include the structure and function of OM lipids and porins, the impact of antibiotic resistance mechanisms on OM permeability, and the role of specific mutations and modifications in reducing antibiotic susceptibility. The review highlights the importance of understanding these mechanisms to develop more effective antibiotic therapies and new antibiotics targeting OM components.