The rise of antibiotic resistance is a pressing global health concern. Bacteria have evolved clever mechanisms to evade the effects of antibiotics, rendering many treatments ineffective. This resistance arises from a combination of genetic mutations, horizontal gene transfer, and environmental adaptations. At the heart of this issue are several key mechanisms. Some bacteria produce enzymes that degrade antibiotics, like β-lactamases that break down β-lactam antibiotics. Others modify their target sites, such as altering ribosomal proteins to evade antibiotic binding. Efflux pumps are another strategy, actively removing antibiotics from the cell. Reduced permeability and biofilm formation also contribute to resistance. This review explores the mechanisms of antibiotic resistance with emphasis on understanding the molecular and genetic basis of bacterial resistance. Research has revealed the intricate molecular basis of these mechanisms. Genetic mutations in target genes, such as gyrA, can confer resistance to fluoroquinolones. Horizontal gene transfer spreads resistance genes via plasmids, transposons, or integrons, accelerating the spread of resistance. Enzyme-mediated degradation is a potent strategy, with β-lactamases hydrolyzing hydrolysing β-lactam antibiotics and aminoglycoside-modifying enzymes inactivating aminoglycosides. The findings highlight the complexity of antibiotic resistance. Efflux pumps, like AcrAB-TolC, are overexpressed in resistant strains, reducing intracellular antibiotic concentrations. Target modifications, such as altered penicillin-binding proteins, confer β-lactam resistance. Biofilms, with their protective extracellular matrices, shield bacteria from antibiotics and host defensesdefences. In the end, understanding these mechanisms is crucial for developing effective strategies to combat resistance. A One Health approach, combining antibiotic stewardship, surveillance, and novel therapeutic development, is essential to address this global threat. By unravelling the molecular basis of resistance, we can develop targeted therapies and stay ahead of the evolving bacterial threat.