The development of antimicrobial resistance among gram-negative pathogens has been progressive and relentless. Pathogens of particular concern include extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Classic agents used to treat these pathogens have become outdated. Of the few new drugs available, many have already become targets for bacterial mechanisms of resistance. This review describes the current approach to infections due to these resistant organisms and elaborates on the available treatment options.