The emergence of new human pathogens and increasing antimicrobial resistance in well-established pathogens are critical public health concerns. Unfortunately, the pipeline of new antimicrobial candidates remains remarkably lean for molecules active against increasingly problematic Gram-negative bacterial pathogens, such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although a number of new anti-Gram-negative antibacterial agents are likely to be introduced soon for clinical use, they will not represent a quantum leap in our ability to effectively treat these human pathogens of great concern. New classes of antimicrobials with novel mechanisms of action and new approaches to increasing the effectiveness of traditional antimicrobials are urgently needed. Renewed research and development efforts must become a priority, lest we fall further behind in our therapeutic initiatives.