The ongoing problem of emerging antimicrobial resistance has been likened to a balloon where settling one specific issue results in a 'bulge' of even worse problems. However, much has been learned about how to best use our critical antibacterial agents in ways to avoid or even repair some of the resistance damage that has been done. A compilation of current literature strongly suggests that to slow the development of resistance to antimicrobial agents it is optimal to use drugs with more than one mechanism of action or target, to prescribe those with demonstrated ability to minimise or reverse resistance problems, and to avoid underdosing of potent antibiotics. The most recent information also indicates that it is best to limit empirical use of beta-lactam plus fluoroquinolone combination therapy, since these two classes activate some common resistance responses, and using them together can facilitate multidrug resistance in important pathogens, particularly Pseudomonas aeruginosa and Acinetobacter species. This review discusses the role of each major antimicrobial class on resistance development and presents specific strategies for combating the growing problem of multidrug-resistant bacteria. We now have the knowledge to better manage our antimicrobial agent prescribing practices, but finding the will and resources to apply our understanding remains a formidable challenge.