The incidence of Gram-negative pathogens resistant to multiple antibiotics and multiple classes of antibiotics is increasing and the resultant deficit in effective therapeutic agents emphasizes the urgent need for novel agents and novel therapeutic approaches to the treatment of Gram-negative infectious disease. While developing versions of existing agents able to overcome resistance, or targeting resistance itself are strategies being considered to deal with multidrug resistance, genomic approaches will ultimately provide a multitude of novel targets for the development of new classes of agents likely to be unaffected by existing resistance mechanisms. The use of 'natural' antibacterials such as cationic antimicrobial peptides and bacteriophage as therapeutic agents is also being pursued. With an increased understanding of the infection process, immunomodulation and vaccinology are increasingly useful approaches to infectious disease management in the face of increasing antimicrobial resistance. Finally, there is a need to rigorously implement appropriate prescribing and infection control practices, to minimize the risk of resistance development and spread. Clearly, the antibiotic era has not heralded the defeat of infectious disease and prudent use of novel therapies is imperative if we are to avoid entering the post-antimicrobial era.