Despite the relevance of infectious disease as main causes of human morbidity and mortality, the development of new antibacterials is not among the highest priorities for pharmaceutical companies. Regulatory and economic issues, together with the lack of novel targets, might justify the reduced rate of discovery of new antimicrobials. With the increasing number of antibiotic resistant pathogens, the mechanisms of resistance appear as appealing alternatives for developing new drugs. Defining the elements that contribute to the characteristic phenotype of susceptibility to antibiotics of a given bacterial species, will serve to find those targets. Recent information on the elements forming part of bacterial intrinsic resistomes and on the inhibitors of resistance currently under development are presented. The possibility of developing new therapeutic procedures based on the administration, together with antibiotics of specific metabolic intermediates capable of increasing the susceptibility to antibiotics by altering bacterial physiology, are also discussed.