Infections due to multidrug-resistant (MDR) organisms continue to increase, and the antimicrobial pipeline remains unacceptably lean. Given this challenge, it is has become necessary to use older antimicrobials for treatment of MDR pathogens despite concerns regarding toxicity and the lack of clinical efficacy data. In some cases, older antimicrobials offer potential advantages compared with new agents, including lower cost and better in vitro activity. In this review, we focus on the pharmacology, in vitro activity, and clinical experience of older agents, including colistin, minocycline, trimethoprim-sulfamethoxazole, and fosfomycin. We also discuss some new antimicrobial agents that are used to treat MDR pathogens. As MDR pathogens continue to outpace the development of new antimicrobials, it will become imperative to develop strategies regarding the optimal use of older agents in terms of monotherapy versus combination therapy, dosing regimens, and treatment of invasive infections caused by these pathogens.