Regulatory guidelines for clinical development of antibacterial drugs have a major impact on decisions regarding research, influencing the degree to which novel targets are pursued, the choice of lead compounds, the spectrum of activity, as well as the dose. It is disconcerting that as pharmaceutical firms abandon antibacterial research and development, and expertise is lost from clinical, regulatory and commercial functions, biotechnology firms focus on easier, Gram-positive targets, which require limited clinical development, and expect pharmaceutical firms that have retreated from antibacterials to in-license compounds with restricted uses. Guidelines and incentives are needed to encourage development of agents targeted against the growing problem of Gram-negative bacterial resistance, as broad-spectrum drugs face even greater hurdles.