Antibiotics represent one of the most successful forms of therapy in medicine. But the efficiency of antibiotics is compromised by a growing number of antibiotic-resistant pathogens. Antibiotic resistance, which is implicated in elevated morbidity and mortality rates as well as in the increased treatment costs, is considered to be one of the major global public health threats (www.who.int/drugresistance/en/) and the magnitude of the problem recently prompted a number of international and national bodies to take actions to protect the public (http:// ec.europa.eu/dgs/health_consumer/docs/road-map-amr_en.pdf: http://www.who.int/drugresistance/amr_global_action_plan/en/; http://www.whitehouse.gov/sites/default/files/docs/carb_nation-al_strategy.pdf). Understanding the mechanisms by which bacte-ria successfully defend themselves against the antibiotic assault represent the main theme of this eBook published as a Research Topic in Frontiers in Microbiology: Antimicrobials, Resistance, and Chemotherapy. The articles in the eBook update the reader on various aspects and mechanisms of antibiotic resistance. A better understanding of these mechanisms should facilitate the development of means to potentiate the efficacy and increase the lifespan of antibiotics while minimizing the emergence of antibiotic resistance. The multidrug efflux systems contribute significantly to the increased resistance to multiple antibiotics in bacteria. A major challenge in developing efficacious antibiotics against drug-resistant pathogens is to identify compounds that can counteract the efflux functions. The wealth of bacterial genomics informa-tion available suggests the presence of a variety of efflux systems in bacteria. Even a single bacterium may possess multiple efflux transporters of different families, with the overlapping substrate spectra. Accumulating evidence has indicated that the MexXY multidrug efflux system is a primary determinant of aminogly-coside resistance in Pseudomonas aeruginosa. Morita et al. (2012) provided a timely review on the P. aeruginosa MexXY pump and other aminoglycoside efflux pumps in a range of different bacte-ria. The expression of bacterial multidrug efflux system is usually controlled by transcriptional regulators that either repress or acti-vate the transcription of the multidrug efflux genes. The articles by Usui et al. (2013) and Deng et al. (2013) further illustrated the complexity of regulation of multidrug efflux systems. However, the importance of multidrug efflux system may not be overstated for a specific antibiotic or organism, which is supported by the findings of Baucheron et al. (2014). β-lactam antibiotics, which inhibit the biosynthesis of bacterial cell wall, are the most widely available antibiotics used to treat a number of bacterial infections. Resistance to β-lactam antibi-otics, however, has become a worldwide health care problem. Production of β-lactamases is a major and threatening resistance mechanism toward β-lactam antibiotics. Epidemiological work by Chuma et al. (2013) demonstrated a recent emergence of β-lactamase-mediated cefotaxime resistance in Salmonella enetrica Serovar Infantis. To counteract β-lactam resistance in pathogenic bacteria, extensive research in the past three decades has focused on the discovery of novel compounds inhibiting the β-lactamase function. Watkins et al. (2013) reviewed the novel β-lactamase inhibitors that are close to being introduced in the clinical prac-tice. Despite the successful development of β-lactamase inhibitors for the combination therapy, the use of β-lactamase inhibitors is still challenged by the variable affinity of inhibitors to different β-lactamases and by the vast quantity of β-lactamases produced by the resistant strains. To address this issue and optimize the exist-ing β-lactam-based therapy, Zeng and Lin (2013) proposed to inhibit the induction of β-lactamases by targeting the key players required for β-lactamase induction, such as lytic transglycosylase. Aminoglycosides are another class of clinically important antibiotics for treating various bacterial pathogens. The increas-ing resistance of clinical isolates against aminoglycosides, how-ever, has compromised the effectiveness of this class of antibiotics. A major mechanism of aminoglycoside resistance is the produc-tion of aminoglycoside-modifying enzymes. Two enzymes with aminoglycoside-modifying activities are discussed in this research topic. Shi et al. (2013) provided a comprehensive overview of the structure of aminoglycoside kinase and reported on the recent progress in the discovery of aminoglycoside phosphotransferase inhibitors using structure-guided strategies. Aminoglycoside 6 -N-acetyltransferase type Ib is another clinically important